From 896790390a14f0da9419e06b505581d2d2209870 Mon Sep 17 00:00:00 2001 From: nkoch1 Date: Sun, 16 Apr 2023 23:16:34 -0400 Subject: [PATCH] add summary_fig.py as a tenative summary figure --- Figures/AUC_correlation_letters.py | 4 +- Figures/diversity_in_firing.py | 2 +- Figures/firing_characterization.py | 2 +- Figures/ramp_firing_letters.py | 2 +- Figures/rheobase_correlation_letters.py | 4 +- .../simulation_model_comparison_letters.py | 4 +- Figures/summary_diagram.png | Bin 0 -> 729742 bytes Figures/summary_fig.py | 387 +++ .../For_Submission/Koch_reviewer_comments.pdf | Bin 91510 -> 284081 bytes .../Koch_reviewer_comments.synctex.gz | Bin 20720 -> 21234 bytes .../For_Submission/Koch_reviewer_comments.tex | 11 +- .../For_Submission/summary_fig.jpg | Bin 0 -> 182782 bytes .../For_Submission/summary_fig.pdf | Bin 0 -> 118920 bytes Frontiers_manuscript/ref.bib | 2423 ----------------- 14 files changed, 406 insertions(+), 2433 deletions(-) create mode 100644 Figures/summary_diagram.png create mode 100644 Figures/summary_fig.py create mode 100644 Frontiers_manuscript/For_Submission/summary_fig.jpg create mode 100644 Frontiers_manuscript/For_Submission/summary_fig.pdf delete mode 100644 Frontiers_manuscript/ref.bib diff --git a/Figures/AUC_correlation_letters.py b/Figures/AUC_correlation_letters.py index cd49d06..5d6596c 100644 --- a/Figures/AUC_correlation_letters.py +++ b/Figures/AUC_correlation_letters.py @@ -538,6 +538,6 @@ ax2.text(-0.075, 1.35, string.ascii_uppercase[8], transform=ax2.transAxes, size= #save fig.set_size_inches(cm2inch(20.75,12)) -fig.savefig('./Figures/AUC_correlation.pdf', dpi=fig.dpi) #pdf #eps -# fig.savefig('./Figures/AUC_correlation.png', dpi=fig.dpi) #pdf #eps +# fig.savefig('./Figures/AUC_correlation.pdf', dpi=fig.dpi) #pdf #eps +fig.savefig('./Figures/AUC_correlation.jpg', dpi=fig.dpi) #pdf #eps plt.show() diff --git a/Figures/diversity_in_firing.py b/Figures/diversity_in_firing.py index ce02dad..e9ddba8 100644 --- a/Figures/diversity_in_firing.py +++ b/Figures/diversity_in_firing.py @@ -188,7 +188,7 @@ for i in range(0,len(models)): spike_axs[i].text(-0.18, 1.2, string.ascii_uppercase[i], transform=spike_axs[i].transAxes, size=10, weight='bold') # save fig.set_size_inches(cm2inch(17.6,20)) -fig.savefig('./Figures/diversity_in_firing.pdf', dpi=fig.dpi) #pdf # eps +fig.savefig('./Figures/diversity_in_firing.jpg', dpi=fig.dpi) #pdf # eps # fig.savefig('./Figures/diversity_in_firing.png', dpi=fig.dpi) #pdf # eps plt.show() diff --git a/Figures/firing_characterization.py b/Figures/firing_characterization.py index a02f8dd..ad67abe 100644 --- a/Figures/firing_characterization.py +++ b/Figures/firing_characterization.py @@ -365,5 +365,5 @@ ax3_BR.annotate('', (0.7, 75), (0.8, 37.5), arrowprops=dict(arrowstyle="<|-", co fig.set_size_inches(cm2inch(8.5,12)) -fig.savefig('./Figures/firing_characterization_arrows.png', dpi=fig.dpi, bbox_inches='tight') #, dpi=fig.dpi #pdf #eps +fig.savefig('./Figures/firing_characterization_arrows.jpg', dpi=300, bbox_inches='tight') #, dpi=fig.dpi #pdf #eps plt.show() diff --git a/Figures/ramp_firing_letters.py b/Figures/ramp_firing_letters.py index 9888ec9..1913fad 100644 --- a/Figures/ramp_firing_letters.py +++ b/Figures/ramp_firing_letters.py @@ -317,6 +317,6 @@ for i in range(0,len(models)): #save fig.set_size_inches(cm2inch(17.6,22)) -fig.savefig('./Figures/ramp_firing.png', dpi=fig.dpi)#pdf #eps +fig.savefig('./Figures/ramp_firing.jpg', dpi=fig.dpi)#pdf #eps plt.show() diff --git a/Figures/rheobase_correlation_letters.py b/Figures/rheobase_correlation_letters.py index cf02cf0..ab1d712 100644 --- a/Figures/rheobase_correlation_letters.py +++ b/Figures/rheobase_correlation_letters.py @@ -608,8 +608,8 @@ ax2.text(-0.075, 1.35, string.ascii_uppercase[8], transform=ax2.transAxes, size= # save fig.set_size_inches(cm2inch(20.75,12)) -fig.savefig('./Figures/rheobase_correlation.pdf', dpi=fig.dpi) -# fig.savefig('./Figures/rheobase_correlation.png', dpi=fig.dpi) #bbox_inches='tight', dpi=fig.dpi # eps # pdf +# fig.savefig('./Figures/rheobase_correlation.pdf', dpi=fig.dpi) +fig.savefig('./Figures/rheobase_correlation.jpg', dpi=fig.dpi) #bbox_inches='tight', dpi=fig.dpi # eps # pdf plt.show() diff --git a/Figures/simulation_model_comparison_letters.py b/Figures/simulation_model_comparison_letters.py index 6e6824f..7bba165 100644 --- a/Figures/simulation_model_comparison_letters.py +++ b/Figures/simulation_model_comparison_letters.py @@ -269,7 +269,7 @@ axr1.text(-0.27, 1.075, string.ascii_uppercase[j+1], transform=axr1.transAxes, s # save fig.set_size_inches(cm2inch(22.2,15)) -fig.savefig('./Figures/simulation_model_comparison.pdf', dpi=fig.dpi) #eps -# fig.savefig('./Figures/simulation_model_comparison.png', dpi=fig.dpi) #eps +# fig.savefig('./Figures/simulation_model_comparison.pdf', dpi=fig.dpi) #eps +fig.savefig('./Figures/simulation_model_comparison.jpg', dpi=fig.dpi) #eps plt.show() diff --git a/Figures/summary_diagram.png b/Figures/summary_diagram.png new file mode 100644 index 0000000000000000000000000000000000000000..2094d92ebedd68134d4853e911a0c8e7d23deb74 GIT binary patch literal 729742 zcmeEtcRZY1yS5M^h)AMD1QCf&gdloE^j=1r=n=geqYWWJB5Jfm@14;{9W6*CdKqnu z5_R-$48HMwXYc*KU%dOA-~RjjfoIlZ=9#tDz3y^d*Zo0VRqh(e9TGe|ylV>bFEsJ+ z$arx-{KQvqBX_x66L5d7I?3z1;^DoNJ^#5x86z!)hj$N8;f0j8htVn$oMZ?X+uySF z+Gw;eU`c-RiQ@UY%fyXu?>CZgz%$ZJq%;`lFmLiGHC|BU2WUPgPJZx=cv<|*7iE?~ z?~VDSgDLM%X%cByd0%xo9xJ@&tLUAw^+Sj(Uay6Mjy={Wi13N;y}|oOzj)u{OI*Hv zMI&B``5%75n>U=#-uMUp(|6n(11aj0+3qrBJ5%aNNLEQ@#P zGR3q1_-h*PGFRR-3+28q@<44d7SedKvb>^Y^&;)W>t4sR&og++!h{!nfWHP8F49w~ zNkoMIeYk4&yJcm+(l_zQUdzTk$%W+sC)a(wqr|St-49jcRmF;1`5JZWow*zm!rM)T zA*lZ_9X1-=bh>EpA|n2qr^#J?N>7tuJ5hPqe^6yT%+Rg>Irn=7-(Ie9L&kJ7o{U^z zeomc&f^ZpT+&-6`Z4_lB#dt-B^5S&Grv?{}b*@}|^RE!^Q}ZU;q%^al0w`e7?ckIS zg&HI28}G!&vq(xB4-X3#78Mzxn$A8dDnv-#yl63TV~6sW@X5Hy|8A?!_wdl^5^J-` zHL9dXMiFw4B&$>(iB&4jb>wo2-Pb$WuRzKGNQn0k*VpTx`Aex1UHMO+H{C`^%v;L$ zH+J!V4Q5)JFlqX^B@jlZytKO14}rn+M(R|NG{9t&Ob2<6l z|8VM?>{_rJr> zq9Fm7C@8ko(KUvaoXmVz><*1hqUj6pk9~Ks<(*049{7Xczk8sBw#nEmx7YTR#mdHx zJhj1XNgkD`sPt`*1`akh#N;j3rBJ1aNWV16F~SjwiwzE|i!+h4*!Q>on{B(Dj4wJ8 zZ`0O=G}w6!$3jkGLFOvR&kS`oPLBu+i1X zSgpyc{+RNPsU&OvX4EYWL_pfM0z7;rRd8n}Ur@mgj7Dw^1Xuv+vxF^vc{V<>E<53uC}~ zAw4j&wXc;{0z;K6DL|UStTY`teIoxKO`yqi#zPAF7JGzPLBjUyFuM4XzS4WJ+rGM{ z*?b-Cw()E0sQ!_)aBS$0h`wbS#>X#G&33P$8K zj6FFGuqM5sM#}hPEB_r>7PUS7;UX*Jz|AOf+tu~Iu`;FR1cIf#Cda-VKmF`29VbT0 z=?$atxh<=mIJ0gsuOjLcVSr!l9H^aDZuy(cT&y^ge*e}?>Ig;90qE{CwEB#j{^q#u z;>04Oui6IBSbEXwi=(6C{Kjl)LTcjLnVyRIjm1pK(_ITt^}*79XGx^r8`P%nX%wGV zViT~$<3)?_siNwKDstMBad@M4JkleHrKhVe2hfh`B-pU&ujO}}6dv4H#mIYlq+H~n zO!CgF`Twc_X6$Y1EU`NG&R9eeK5vqOqg`O+S zKmtNSNi~2<@e?xU9oW0c&fi}K$`A^Z`ss-?yp_2i(YZZ^E6Rfou#dg|c0Vu4HHTCq znzXVGrbex20*zv65K7{jIUsUkH)%2>fUZEnz^Tt(XRh`3&&S90WUJ!_`Jdl8wX?hk z#TcxotV@t`a}9>H0|k~hA9HXQ=$iRtna$lVjt$g(_^@haXN%2Iv0PQeFHVzxPPTDO z-G_kMF27G4Wn47bKpA+Mr~qCfQ~$9LG&wdXu=mZ*VxgV$>FCu*qf)-6Y^qG=&wrnn zY!R;3zad&BcKhOR@&BSMui|B{hUqP@yV9++rbwq!zD(yp)v)#{UBX2UQs+7RU-RrT` zBL=}FeiMzT&X8#>Dh38FwI(@HaNHQrX|e+>5Y0u*x0ZKz1r_|QfcA5je-paE!0qg; z;X$eqb$8k>V9U<MUVWm+hjH`zLT=X=8a&z(@liP0n{Grz5MAlZ9pSB)QYK%vU-pT+*^`z;$l# zm-vt2k;(jJo%epr*E;p{m|lH#g^UvH1HpvG#*BOJ`^()lLY(XZiuEvE+oPRC0aMK& zEY@cjfpC=Bq$2r9rXlAY?@)VyFVp_6{Owt!{^Jp*wgA@dJ^HTXqzoDcPh(r7Uc}+m z#5jrnjvL-B= z5h&f%rq^(@Tg4qHu*%LBZ7cs>IBCwK z-dst}p4ja>gRgU34!*)B_T3339<=1J=W2*j zX<8?n>zx(OR%?lJ>v;#{nWRz?Fi6f*OA}x?lDG7Y_aSR%esQ*;s2x(R!hxB4Z*2sU z4hW+*at@#CNy%|-a*M&o$9_SiOZ10czhJrx=f3IaGM~@i`X>J~&c0WK<6zWwK&$z4 zw^>jA)#Ha<^od#Tzp2COpMfmiHb_ZeI(mC5*9iy{_(Zjw*)=lDSJn}P%drkEs4fUWa0Tq z8t%M}-re0m=}227y0}EoyIGCaz~y}}!4o`{Q^F-I%FVdnmz!EdO?-IORirF5-R6H` zf?#rPz{-XtVHe%~b8Pbq=~K~u@1jUiKdoA`o2@aQ88T6m*d!_!7zZKF5@#HRE|=8pi?J`EhaNVd7jea`ciKa$E@}VOL}kFj+& zeI-Jv$gKF(mzfIDd{lStWEB+1?s*)$&7GwbS1+i>t``hW&askp6PajV^qrYCab>{! zBpn8l-)H+TZrUWZIkO3(!15D`EiyHU1h6Xn(s;lhxR?VRl8?nOZk+n434O?EwO zgLfDlER+4 z+e=*2f@xEyzJN9Bp^p(I?%?@@g99yB^ZG6@!g{30d3%p;sk^kL$fvtBH&-nM2bKu0 z@fzB>-<8&AF0}XvTggX3)g8f5%}?gBQD005_WFbN>M8FsT=Tp1tQtS}$-SFF6~>NGz-0Dux2hFK4GnThY@f(1NhZ*xvopDaLpD$OSt zvctm=dy=ABzP|8n5y|QuBsBA~^NDEv?kw|$?a!JQG9B;gX5O_H$8wBoWVcz)uYvU{ za-Ok&aUO|kQOmBk5pZ`YfFBiB$b}6$8IY?^zf$w9VyH!{2x!CDAMidCu4UiXf(klv z#C4*hI_Chm(o40;tVFfmY2V39tRv)4AMjUz;|;~ljBM_^`O-yp`PbN)ep-2!RJ*9{ z6P8C(+|_ef0!eTE{10UzA>^*cdWK_JMkoo$TJ<0$6C@jl^Al<=JA@YQb!piOfDHDHh#1j28fiNvDNx$fAN@VoEJ%pA5k=

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zTM2C>&hUIpDvBY5`f`lZeQ2>>&pE4=ByEzk5hrW{YwYOnL|WA&AktJ>;=dey(%-@% zH=>**g?cQ4?0g+Ph+M`)a#1Rv9jWbNw~~8;tUskmQWCTy!HNUAR~;l`uGbXK$zmuI zRJ?I2+344(zm*7-;KKsD-$>cNpZqf(m=u6KFRx-&?oyT7Kq@|LGku18_TvQ-z^C|L+k0AItt%_w;`(`(KKx|6|$z nit+!CW&cZ2_5U+1yC*8I{lNs9ABcYp{Cg-Ndq4G_&ddJ~uK 2: + lightness = 2 + if lightness > 1: + return darker(color, 2.0 - lightness) + if lightness < 0: + lightness = 0 + r, g, b = cc.to_rgb(color) + rl = r + (1.0 - lightness) * (1.0 - r) + gl = g + (1.0 - lightness) * (1.0 - g) + bl = b + (1.0 - lightness) * (1.0 - b) + return to_hex((rl, gl, bl)).upper() + + +def plot_sqrt(ax, a=1, b=0.2, c=100, d=0): + x = np.linspace(0, 1, 10000) + y = c * np.sqrt(a * (x - b)) + d + ax.plot(x, y) + ax.set_xlabel('Current [nA]') + ax.set_ylabel('Frequency [Hz]') + ax.set_xlim(0, 1) + ax.set_ylim(0, ax.get_ylim()[1]) + + +def plot_AUC(ax, a=1, b=0.2, c=180, d=0, width=0.2): + x = np.linspace(0, 1, 1000) + y = c * np.sqrt(a * (x - b)) + d + ax.plot(x, y, colorslist[9]) + ax.set_xlabel('Current [nA]') + ax.set_ylabel('Frequency [Hz]') + ax.fill_between(x, y, where=(x <= b + width), color=lighter(colorslist[9], 0.3)) + ax.text(0.3, 15, 'AUC', ha='center') + ax.annotate('', (0.2, 10), (0, 10), arrowprops=dict(arrowstyle="<->")) + ax.text(0.1, 20, 'rheobase', ha='center') + ax.set_xlim(0, 0.5) + ax.set_ylim(0, 100) + ax.yaxis.set_major_locator(ticker.MultipleLocator(50)) + + +def plot_diff_sqrt(ax, a=1, b=0.2, c=100, d=0, a2=1, b2=0.2, c2=100, d2=0): + show_spines(ax, 'lb') + x = np.linspace(0, 1, 10000) + y = c * np.sqrt(a * (x - b)) + d + y2 = c2 * np.sqrt(a2 * (x - b2)) + d2 + ax.plot(x, y, colorslist[9]) + ax.plot(x, y2, colorslist[2]) + ax.set_xlim(0, 1) + ax.set_ylim(0, ax.get_ylim()[1]) + ax.set_xticks([]) + ax.set_yticks([]) + ax.set_xlabel('Current') + ax.set_ylabel('Frequency') + + +def plot_quadrant(ax): + ax.spines['left'].set_position('zero') + ax.spines['bottom'].set_position('zero') + ax.text(1.2, -0.15, '$\\Delta$ rheobase', ha='right') + ax.text(-0.03, 0.7, '$\\Delta$ AUC', ha='right', rotation=90) + ax.tick_params(length=0) + ax.set_xlim(-1, 1) + ax.set_ylim(-1, 1) + ax.annotate('', (1, 0), (-1, 0), arrowprops=dict(arrowstyle="->")) + ax.annotate('', (0, 1), (0, -1), arrowprops=dict(arrowstyle="->")) + ax.set_xticks([-0.5, 0.5]) + a = ax.get_xticks().tolist() + a[0] = '\u2212' + a[1] = '+' + ax.set_xticklabels(a) + ax.set_yticks([-0.5, 0.5]) + b = ax.get_xticks().tolist() + b[0] = '\u2212' + b[1] = '+' + ax.set_yticklabels(b) +# +# #%% +# +# imgplot = plt.imshow(img) +# plt.show() + + + +# %% with legend +scheme_style() +import matplotlib.image as mpimg +img = mpimg.imread('./Figures/summary_diagram.png') +inset_ylim = (0, 100) +lfsize = 8 +fig = plt.figure(figsize=cm2inch(17.2, 12)) +gs = gridspec.GridSpec(14, 3, top=0.95, bottom=0.1, left=0.15, right=0.95, hspace=0.4, wspace=0.2) + +# gs0 = gs[1:13, 2].subgridspec(3, 1, hspace=0.9, wspace=0.25) # width_ratios=[0.3, 0.3,0.3], height_ratios=[0.35], +ax1 = fig.add_subplot(gs[1:4,2]) +ax2 = fig.add_subplot(gs[6:9,2]) +ax3 = fig.add_subplot(gs[11:14,2]) + +ax0 = fig.add_subplot(gs[:, :2]) +# ax1 = fig.add_subplot(gs0[0]) +# ax2 = fig.add_subplot(gs0[1]) +# ax3 = fig.add_subplot(gs0[2]) + +ax0.imshow(img) +show_spines(ax0, '') + + +# ax1.text(-0.95, -0.55, 'GOF/\nLOF?', ha='right') +plot_diff_sqrt(ax1, b2=0.06, c2=65) +ax1.set_ylim(inset_ylim) +ax1.annotate('', (0.225, 7), (0.07, 7), + arrowprops=dict(arrowstyle="<|-", color=colorslist[2], lw=0.5, mutation_scale=5), zorder=-10) # +ax1.annotate('', (0.8, 80), (0.85, 55), + arrowprops=dict(arrowstyle="<|-", color=colorslist[2], lw=0.5, mutation_scale=5), zorder=-10) # +ax1.text(x=0.05, y=95, s='$\\downarrow$ AUC $\downarrow$ rheobase', fontsize=lfsize) + + + +# ax2.text(0.95, 0.35, 'LOF/\nGOF?') +plot_diff_sqrt(ax2, b2=0.4, c2=200) +ax2.set_ylim(inset_ylim) +ax2.annotate('', (0.19, 7), (0.41, 7), + arrowprops=dict(arrowstyle="<|-", color=colorslist[2], lw=0.5, mutation_scale=5), zorder=-10) # +ax2.annotate('', (0.75, 70), (0.6, 90), + arrowprops=dict(arrowstyle="<|-", color=colorslist[2], lw=0.5, mutation_scale=5), zorder=-10) # +ax2.text(x=0.05, y=110, s='$\\uparrow$ AUC $\\uparrow$ rheobase', fontsize=lfsize) +# + + + + +plot_diff_sqrt(ax3, b2=0.09, c2=200) + +# ax3.text(x=-0.9, y=0.7, s='$\\uparrow$ AUC\n$\\downarrow$ rheobase', fontsize=lfsize) +# ax3.text(-0.95, 0.35, 'GOF', ha='right') +ax3.set_ylim(inset_ylim) +ax3.annotate('', (0.225, 7), (0.085, 7), + arrowprops=dict(arrowstyle="<|-", color=colorslist[2], lw=0.5, mutation_scale=5), zorder=-10) # +ax3.annotate('', (0.55, 55), (0.3, 90), + arrowprops=dict(arrowstyle="<|-", color=colorslist[2], lw=0.5, mutation_scale=5), zorder=-10) # +ax3.text(x=0.05, y=110, s='$\\uparrow$ AUC $\\downarrow$ rheobase', fontsize=lfsize) + +# fig.set_size_inches(cm2inch(17, 12)) +fig.savefig('./Figures/summary_fig.pdf', dpi=300, bbox_inches='tight') # , dpi=fig.dpi #pdf #eps +# + +plt.show() + + +# # %% with arrows +# fig = plt.figure(figsize=cm2inch(7, 12)) +# # gs = gridspec.GridSpec(3,6, top=0.95, bottom=0.1, left=0.15, right = 0.95, hspace=0.8, wspace=0.6) +# gs = gridspec.GridSpec(3, 6, top=0.9, bottom=0.05, left=0.15, right=0.9, hspace=0.8, wspace=0.6) +# ax1 = fig.add_subplot(gs[0, 1:]) +# show_spines(ax1, 'lb') +# plot_AUC(ax1, width=0.2) +# ax3 = fig.add_subplot(gs[1:, :]) +# +# # add panel letter labels +# ax1.text(-0.4, 1.2, string.ascii_uppercase[0], transform=ax1.transAxes, size=16, weight='bold') +# ax3.text(-0.15, 1.05, string.ascii_uppercase[1], transform=ax3.transAxes, size=16, weight='bold') +# +# show_spines(ax3, '') +# plot_quadrant(ax3) # plot delineation into quadrants +# +# inset_ylim = (0, 100) +# # top left +# lfsize = 8 +# ax3.text(x=-0.9, y=0.7, s='$\\uparrow$ AUC\n$\\downarrow$ rheobase', fontsize=lfsize) +# ax3.text(-0.95, 0.35, 'GOF', ha='right') +# ax3_TL = ax3.inset_axes([0.07, 0.6, 0.3, 0.2]) +# plot_diff_sqrt(ax3_TL, b2=0.09, c2=200) +# ax3_TL.set_ylim(inset_ylim) +# ax3_TL.annotate('', (0.25, 7), (0.085, 7), +# arrowprops=dict(arrowstyle="<|-", color=colorslist[2], lw=0.5, mutation_scale=5), zorder=-10) # +# ax3_TL.annotate('', (0.55, 55), (0.3, 90), +# arrowprops=dict(arrowstyle="<|-", color=colorslist[2], lw=0.5, mutation_scale=5), zorder=-10) # +# # top right +# ax3.text(x=0.22, y=0.7, s='$\\uparrow$ AUC\n$\\uparrow$ rheobase', fontsize=lfsize) +# ax3.text(0.95, 0.35, 'LOF/\nGOF?') +# ax3_TR = ax3.inset_axes([0.63, 0.6, 0.3, 0.2]) +# plot_diff_sqrt(ax3_TR, b2=0.4, c2=200) +# ax3_TR.set_ylim(inset_ylim) +# ax3_TR.annotate('', (0.17, 7), (0.41, 7), +# arrowprops=dict(arrowstyle="<|-", color=colorslist[2], lw=0.5, mutation_scale=5), zorder=-10) # +# ax3_TR.annotate('', (0.8, 70), (0.6, 90), +# arrowprops=dict(arrowstyle="<|-", color=colorslist[2], lw=0.5, mutation_scale=5), zorder=-10) # +# +# # bottom left +# ax3.text(x=-0.9, y=-0.95, s='$\\downarrow$ AUC\n$\downarrow$ rheobase', fontsize=lfsize) +# ax3.text(-0.95, -0.55, 'GOF/\nLOF?', ha='right') +# ax3_BL = ax3.inset_axes([0.07, 0.15, 0.3, 0.2]) +# plot_diff_sqrt(ax3_BL, b2=0.06, c2=65) +# ax3_BL.set_ylim(inset_ylim) +# ax3_BL.annotate('', (0.25, 7), (0.07, 7), +# arrowprops=dict(arrowstyle="<|-", color=colorslist[2], lw=0.5, mutation_scale=5), zorder=-10) # +# ax3_BL.annotate('', (0.8, 80), (0.85, 55), +# arrowprops=dict(arrowstyle="<|-", color=colorslist[2], lw=0.5, mutation_scale=5), zorder=-10) # +# +# # bottom right +# ax3.text(x=0.22, y=-0.95, s='$\\downarrow$ AUC\n$\\uparrow$ rheobase', fontsize=lfsize) +# ax3.text(0.95, -0.55, 'LOF') +# ax3_BR = ax3.inset_axes([0.63, 0.15, 0.3, 0.2]) +# plot_diff_sqrt(ax3_BR, b2=0.4, c2=60) +# ax3_BR.set_ylim(inset_ylim) +# ax3_BR.annotate('', (0.18, 7), (0.42, 7), +# arrowprops=dict(arrowstyle="<|-", color=colorslist[2], lw=0.5, mutation_scale=5), zorder=-10) # +# ax3_BR.annotate('', (0.7, 75), (0.8, 37.5), +# arrowprops=dict(arrowstyle="<|-", color=colorslist[2], lw=0.5, mutation_scale=5), zorder=-10) # +# +# 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    `c9l<8GH>3`z8Wdggcio3TJSjm6y>*9lKyKL@ee~(drfiMg&IciVe?SCwC z%Xf+T`dO)q@smugiN+jmI<;dpNAKi7uX9@j?J{h~9MV}HlNZO30`_{__{uNi4-o21 zjfl93oFzMuzTgX{Wv6~T-7t2tuswdAMbAfdcRE^EXIr-LE&`Wj@y^%xrORoyDlR$s z;!E1cZFB>9xH^n-J2vqJ$IJ~X{i0EWf>D%R1t-J(n%KeXg>}A)hia2VRJ%1e-_vya z2PYR4Uv+FP@OSm7l(1KOO&BbEEsnoW0xfDfrUDr;5blU~AKy;%4%=;TUx+T-j+L%+ z4KZKrADZ$l^`l;P7Dwt?O79#759Y2#eGP#tu%WzJ%$z>&Jm|#tK1>l>9zngxbLjsD zv@c{CvwP)DE}Jh{;9<0sz+6f^i%2@DyCtk6D}x`K=x@Jh{%MI6R-CL;!67c{!vJL4 zXd;+BfzlE>7wS&mPJWkrkFStUq_(K~;ZeDkwEICP(fQrv+-4vVw&Q3#+=l#V@7)*N z7fr|jZW#~e#(9i?pr9`(5YT`A0dWdvlNfhjs?rw>9$UZmu9f%J9YH;ZnM6hby_Fqz zamO(BL^An+))Y_+_YIZbKz@t&5h=;C&h?qw**VMT0*8jpsbmV7T$pv7JatpuDg%l= zLOz}H`uK%{*!#~l8nk`Vk0(0Bn=KD-khDDck)G{4biAk`S>9@SWLV%?W3*Mutle!A z+8*_a62;QvNYohA*b6wfBLtDP^CbbnF(kS5cIsZ=Lj85(iD_s`rn?y(=R-dp2 zk2oTD`YSZ05!!`7#O%U12RsPUg|GU5_3|(_FvE89co^yNO5LqIMgtv(;!H z=e;`rB9L>q=}%}(tjt`bX5#6=L`vRTD@97YGd|D#k2Dg{=50X!-p5Nx`j(4bo0k9k zpj(r4vPf}WzoiRP7@y*lw!o-|D@!ia@`mvl0-k$&So|?LW%sXxKbrAeVo>!g0oBLUnbAY#7UvUR* z=PMZtJn!WR4RIEKB8H7KI`x3I)N9mnvgO!_`)qv(_G7aZ$gTwT9(L@8Vr}0}h)5!b zx*^_c_O9}6tRhjUGvSs4k*Dm7FAy}y8-E+i!z;3pOsp*Lfj}{$^0;B1O*f(A-f`t^!; zLw6iNM(nAFfNy80$DM`2s}{Zu`-0fds(kBs*)dVHE;)7c=GTvP&;0J?%JmueeItaP z0m(zzmR-o#57G-VzD0Bqamsa+xXC^d=3oXKMUBK#RSAHqf z?q2lzjb)*#K>4?InR{0v!Dj4cnz01}N$Lk*R)HgZ6CpGJC@t1t(3~Svq!f-9W?_9~ zrWnC+`<~k4_gVcMEu3`bJ(ameKF0F&-vJGNC>WOw>>&W5;M&&qcdv~c>4mSqm+|E` z9c2DY6UE2roWP-;*@tZdjDl|y{5=T|oBuNUtU!4t!~=>!R|psb58{m0fdbpvHVG7{ z2%8k}_ywIwssKiWI1@quOq%UXb^rqXf1lYxznJ0~BQ>)(b;dZE8QT#`XcKEvm>3uW zCKR9$I0P#C4_N4LsFV~~P!8>4j{!r$g34B=&fuqDC=_`42&@kleC+OE1{PE^wlH%B z%gFrG7AF4Rje*WER%m;KF~$tcjgSz62*Du2P*EWm6e0}ghX`{)AY448f^vj2UhLA%3^MHZ)B`^`NIru*?s3`dCE!h4i3<`yd2?29Lc>aMw zpb#N3;d3z9uWf;P!cdWO^@L%+^g*a60{^8R(4Xk9Z6Uz-Aivgw!9;*%`4@f=h!6x= z-G9RX@3~*wLLnmO+loVk&h;xM_CH|%Ya9^x|L7Nf4nLR(?AQ5&z{G@qoo5J4T>Mv@ zA;LmX;5YmC*n~yI&%?yd&w&W!+V6%mD1j?0~=n1U0NY%m88{5STN@*a>q+UQnnQFe*|Gj{B+ Channels by Membrane Lipids}, -journal = {Science}, -volume = {304}, -number = {5668}, -pages = {265-270}, -year = {2004}, -doi = {10.1126/science.1094113}, -abstract = {Voltage-gated potassium (Kv) channels control action potential repolarization, interspike membrane potential, and action potential frequency in excitable cells. It is thought that the combinatorial association between distinct α and β subunits determines whether Kv channels function as non-inactivating delayed rectifiers or as rapidly inactivating A-type channels. We show that membrane lipids can convert A-type channels into delayed rectifiers and vice versa. Phosphoinositides remove N-type inactivation from A-type channels by immobilizing the inactivation domains. Conversely, arachidonic acid and its amide anandamide endow delayed rectifiers with rapid voltage-dependent inactivation. The bidirectional control of Kv channel gating by lipids may provide a mechanism for the dynamic regulation of electrical signaling in the nervous system.}} - - - - - @ARTICLE{Menchaca_2012, -AUTHOR={Rodríguez Menchaca, Aldo and Adney, Scott and Zhou, Lei and Logothetis, Diomedes}, -TITLE={Dual Regulation of Voltage-Sensitive Ion Channels by PIP2}, -JOURNAL={Frontiers in Pharmacology}, -VOLUME={3}, -YEAR={2012}, -DOI={10.3389/fphar.2012.00170}, -ISSN={1663-9812}, - -ABSTRACT={Over the past 16 years, there has been an impressive number of ion channels shown to be sensitive to the major phosphoinositide in the plasma membrane, phosphatidylinositol 4,5-bisphosphate (PIP2). Among them are voltage-gated channels, which are crucial for both neuronal and cardiac excitability. Voltage-gated calcium (Cav) channels were shown to be regulated bidirectionally by PIP2. On one hand, PIP2 stabilized their activity by reducing current rundown but on the other hand it produced a voltage-dependent inhibition by shifting the activation curve to more positive voltages. For voltage-gated potassium (Kv) channels PIP2 was first shown to prevent N-type inactivation regardless of whether the fast inactivation gate was part of the pore-forming α subunit or of an accessory β subunit. Careful examination of the effects of PIP2 on the activation mechanism of Kv1.2 has shown a similar bidirectional regulation as in the Cav channels. The two effects could be distinguished kinetically, in terms of their sensitivities to PIP2 and by distinct molecular determinants. The rightward shift of the Kv1.2 voltage dependence implicated basic residues in the S4–S5 linker and was consistent with stabilization of the inactive state of the voltage sensor. A third type of a voltage-gated ion channel modulated by PIP2 is the hyperpolarization-activated cyclic nucleotide-gated (HCN) channel. PIP2 has been shown to enhance the opening of HCN channels by shifting their voltage-dependent activation toward depolarized potentials. The sea urchin HCN channel, SpIH, showed again a PIP2-mediated bidirectional effect but in reverse order than the depolarization-activated Cav and Kv channels: a voltage-dependent potentiation, like the mammalian HCN channels, but also an inhibition of the cGMP-induced current activation. Just like the Kv1.2 channels, distinct molecular determinants underlied the PIP2 dual effects on SpIH, with the proximal C-terminus implicated in the inhibitory effect. The dual regulation of these very different ion channels, all of which are voltage-dependent, points to conserved mechanisms of regulation of these channels by PIP2.} -} - - - - @article{Al-Sabi_2013, - author = {Al-Sabi, Ahmed and Kaza, Seshu Kumar and Dolly, J. Oliver and Wang, Jiafu}, - title = "{Pharmacological characteristics of Kv1.1- and Kv1.2-containing channels are influenced by the stoichiometry and positioning of their α subunits}", - journal = {Biochemical Journal}, - volume = {454}, - number = {1}, - pages = {101-108}, - year = {2013}, - month = {07}, - abstract = "{Voltage-sensitive neuronal Kv1 channels composed of four α subunits and four associated auxiliary β subunits control neuronal excitability and neurotransmission. Limited information exists on the combinations of α subunit isoforms (i.e. Kv1.1–1.6) or their positions in the oligomers, and how these affect sensitivity to blockers. It is known that TEA (tetraethylammonium) inhibits Kv1.1 channels largely due to binding a critical tyrosine (Tyr379) in the pore, whereas Val381 at the equivalent location in Kv1.2 makes it insensitive. With the eventual aim of developing blockers for therapeutic purposes, Kv1.1 and 1.2 α subunit genes were concatenated to form combinations representing those in central neurons, followed by surface expression in HEK (human embryonic kidney)-293 cells as single-chain functional proteins. Patch-clamp recordings demonstrated the influences of the ratios and positioning of these α subunits on the biophysical and pharmacological properties of oligomeric K+ channels. Raising the ratio of Kv1.1 to Kv1.2 in Kv1.2-1.2-1.1-1.2 led to the resultant channels being more sensitive to TEA and also affected their biophysical parameters. Moreover, mutagenesis of one or more residues in the first Kv1.2 to resemble those in Kv1.1 increased TEA sensitivity only when it is adjacent to a Kv1.1 subunit, whereas placing a non-interactive subunit between these two diminished susceptibility. The findings of the present study support the possibility of α subunits being precisely arranged in Kv1 channels, rather than being randomly assembled. This is important in designing drugs with abilities to inhibit particular oligomeric Kv1 subtypes, with the goal of elevating neuronal excitability and improving neurotransmission in certain diseases.}", - issn = {0264-6021}, - doi = {10.1042/BJ20130297}, -} - -@Article{Bryson_2020, - author = {Alexander Bryson and Robert John Hatch and Bas-Jan Zandt and Christian Rossert and Samuel F. Berkovic and Christopher A. Reid and David B. Grayden and Sean L. Hill and Steven Petrou}, - journal = {Proceedings of the National Academy of Sciences}, - title = {GABA-mediated tonic inhibition differentially modulates gain in functional subtypes of cortical interneurons}, - year = {2020}, - number = {6}, - pages = {3192-3202}, - volume = {117}, - abstract = {The binding of GABA (γ-aminobutyric acid) to extrasynaptic GABAA receptors generates tonic inhibition that acts as a powerful modulator of cortical network activity. Despite GABA being present throughout the extracellular space of the brain, previous work has shown that GABA may differentially modulate the excitability of neuron subtypes according to variation in chloride gradient. Here, using biophysically detailed neuron models, we predict that tonic inhibition can differentially modulate the excitability of neuron subtypes according to variation in electrophysiological properties. Surprisingly, tonic inhibition increased the responsiveness (or gain) in models with features typical for somatostatin interneurons but decreased gain in models with features typical for parvalbumin interneurons. Patch-clamp recordings from cortical interneurons supported these predictions, and further in silico analysis was then performed to seek a putative mechanism underlying gain modulation. We found that gain modulation in models was dependent upon the magnitude of tonic current generated at depolarized membrane potential—a property associated with outward rectifying GABAA receptors. Furthermore, tonic inhibition produced two biophysical changes in models of relevance to neuronal excitability: 1) enhanced action potential repolarization via increased current flow into the dendritic compartment, and 2) reduced activation of voltage-dependent potassium channels. Finally, we show theoretically that reduced potassium channel activation selectively increases gain in models possessing action potential dynamics typical for somatostatin interneurons. Potassium channels in parvalbumin-type models deactivate rapidly and are unavailable for further modulation. These findings show that GABA can differentially modulate interneuron excitability and suggest a mechanism through which this occurs in silico via differences of intrinsic electrophysiological properties.}, - doi = {10.1073/pnas.1906369117}, -} - - - @article{Bayraktar, -author = {Bayraktar, Erva and Liu, Yuanyuan and Sonnenberg, Lukas and Hedrich, Ulrike B. S. and Sara, Yildirim and Eltokhi, Ahmed and Lyu, Hang and Lerche, Holger and Wuttke, Thomas V. and Lauxmann, Stephan}, -title = {In vitro effects of eslicarbazepine (S-licarbazepine) as a potential precision therapy on SCN8A variants causing neuropsychiatric disorders}, -journal = {British Journal of Pharmacology}, -volume = {n/a}, -number = {n/a}, -year = {2022}, -pages = {}, -keywords = {developmental and epileptic encephalopathy, eslicarbazepine, epilepsy, NaV1.6, precision medicine, SCN8A, S-licarbazepine, sodium channel blocker}, -abstract = {Background and Purpose Variants in SCN8A, the NaV1.6 channel's coding gene, are characterized by a variety of symptoms, including intractable epileptic seizures, psychomotor delay, progressive cognitive decline, autistic features, ataxia or dystonia. Standard anticonvulsant treatment has a limited impact on the course of disease. Experimental Approach We investigated the therapeutic potential of eslicarbazepine (S-licarbazepine; S-lic), an enhancer of slow inactivation of voltage gated sodium channels, on two variants with biophysical and neuronal gain-of-function (G1475R and M1760I) and one variant with biophysical gain-of-function but neuronal loss-of-function (A1622D) in neuroblastoma cells and in murine primary hippocampal neuron cultures. These three variants cover the broad spectrum of NaV1.6-associated disease and are linked to representative phenotypes of mild to moderate epilepsy (G1475R), developmental and epileptic encephalopathy (M1760I) and intellectual disability without epilepsy (A1622D). Key Results Similar to known effects on NaV1.6 wildtype channels, S-lic predominantly enhances slow inactivation on all tested variants, irrespective of their particular biophysical mechanisms. Beyond that, S-lic exhibits variant-specific effects including a partial reversal of pathologically slowed fast inactivation dynamics (A1622D and M1760I) and a trend to reduce enhanced persistent Na+ current by A1622D variant channels. Furthermore, our data in primary transfected neurons reveal that not only variant-associated hyperexcitability (M1760I and G1475R) but also hypoexcitability (A1622D) can be modulated by S-lic. Conclusions and Implications S-lic has not only substance-specific effects but also variant-specific effects. Personalized treatment regimens optimized to achieve such variant-specific pharmacological modulation may help to reduce adverse side effects and improve the overall therapeutic outcome of SCN8A-related disease.} -} - - - - - -@Article{Clerx2019, - author = {Clerx, Michael and Beattie, Kylie A. and Gavaghan, David J. and Mirams, Gary R.}, - journal = {Biophysical Journal}, - title = {Four {Ways} to {Fit} an {Ion} {Channel} {Model}}, - year = {2019}, - issn = {0006-3495}, - month = dec, - number = {12}, - pages = {2420--2437}, - volume = {117}, - abstract = {Mathematical models of ionic currents are used to study the electrophysiology of the heart, brain, gut, and several other organs. Increasingly, these models are being used predictively in the clinic, for example, to predict the risks and results of genetic mutations, pharmacological treatments, or surgical procedures. These safety-critical applications depend on accurate characterization of the underlying ionic currents. Four different methods can be found in the literature to fit voltage-sensitive ion channel models to whole-cell current measurements: method 1, fitting model equations directly to time-constant, steady-state, and I-V summary curves; method 2, fitting by comparing simulated versions of these summary curves to their experimental counterparts; method 3, fitting to the current traces themselves from a range of protocols; and method 4, fitting to a single current trace from a short and rapidly fluctuating voltage-clamp protocol. We compare these methods using a set of experiments in which hERG1a current was measured in nine Chinese hamster ovary cells. In each cell, the same sequence of fitting protocols was applied, as well as an independent validation protocol. We show that methods 3 and 4 provide the best predictions on the independent validation set and that short, rapidly fluctuating protocols like that used in method 4 can replace much longer conventional protocols without loss of predictive ability. Although data for method 2 are most readily available from the literature, we find it performs poorly compared to methods 3 and 4 both in accuracy of predictions and computational efficiency. Our results demonstrate how novel experimental and computational approaches can improve the quality of model predictions in safety-critical applications.}, - doi = {10.1016/j.bpj.2019.08.001}, - file = {ScienceDirect Full Text PDF:https\://www.sciencedirect.com/science/article/pii/S0006349519306666/pdfft?md5=116e21c18622fee37de1cd056c795e82&pid=1-s2.0-S0006349519306666-main.pdf&isDTMRedir=Y:application/pdf}, - language = {english}, - -} - - -@Article{Balachandar2018, - author = {Balachandar, Arjun and Prescott, Steven A.}, - journal = {The Journal of Physiology}, - title = {Origin of heterogeneous spiking patterns from continuously distributed ion channel densities: a computational study in spinal dorsal horn neurons}, - year = {2018}, - issn = {1469-7793}, - number = {9}, - pages = {1681--1697}, - volume = {596}, - abstract = {Key points Distinct spiking patterns may arise from qualitative differences in ion channel expression (i.e. when different neurons express distinct ion channels) and/or when quantitative differences in expression levels qualitatively alter the spike generation process. We hypothesized that spiking patterns in neurons of the superficial dorsal horn (SDH) of spinal cord reflect both mechanisms. We reproduced SDH neuron spiking patterns by varying densities of KV1- and A-type potassium conductances. Plotting the spiking patterns that emerge from different density combinations revealed spiking-pattern regions separated by boundaries (bifurcations). This map suggests that certain spiking pattern combinations occur when the distribution of potassium channel densities straddle boundaries, whereas other spiking patterns reflect distinct patterns of ion channel expression. The former mechanism may explain why certain spiking patterns co-occur in genetically identified neuron types. We also present algorithms to predict spiking pattern proportions from ion channel density distributions, and vice versa. Abstract Neurons are often classified by spiking pattern. Yet, some neurons exhibit distinct patterns under subtly different test conditions, which suggests that they operate near an abrupt transition, or bifurcation. A set of such neurons may exhibit heterogeneous spiking patterns not because of qualitative differences in which ion channels they express, but rather because quantitative differences in expression levels cause neurons to operate on opposite sides of a bifurcation. Neurons in the spinal dorsal horn, for example, respond to somatic current injection with patterns that include tonic, single, gap, delayed and reluctant spiking. It is unclear whether these patterns reflect five cell populations (defined by distinct ion channel expression patterns), heterogeneity within a single population, or some combination thereof. We reproduced all five spiking patterns in a computational model by varying the densities of a low-threshold (KV1-type) potassium conductance and an inactivating (A-type) potassium conductance and found that single, gap, delayed and reluctant spiking arise when the joint probability distribution of those channel densities spans two intersecting bifurcations that divide the parameter space into quadrants, each associated with a different spiking pattern. Tonic spiking likely arises from a separate distribution of potassium channel densities. These results argue in favour of two cell populations, one characterized by tonic spiking and the other by heterogeneous spiking patterns. We present algorithms to predict spiking pattern proportions based on ion channel density distributions and, conversely, to estimate ion channel density distributions based on spiking pattern proportions. The implications for classifying cells based on spiking pattern are discussed.}, - copyright = {© 2018 The Authors. The Journal of Physiology published by John Wiley \& Sons Ltd on behalf of The Physiological Society}, - doi = {10.1113/JP275240}, - file = {Full Text PDF:https\://onlinelibrary.wiley.com/doi/pdfdirect/10.1113/JP275240:application/pdf}, - keywords = {spiking pattern, Spinal cord, dorsal horn, Neuronal excitability, classification, computational modeling}, - language = {english}, - shorttitle = {Origin of heterogeneous spiking patterns from continuously distributed ion channel densities}, -} - - -@Article{Tripathy2017, - author = {Tripathy, Shreejoy J. and Toker, Lilah and Li, Brenna and Crichlow, Cindy-Lee and Tebaykin, Dmitry and Mancarci, B. Ogan and Pavlidis, Paul}, - journal = {PLOS Computational Biology}, - title = {Transcriptomic correlates of neuron electrophysiological diversity}, - year = {2017}, - issn = {1553-7358}, - month = oct, - number = {10}, - pages = {e1005814}, - volume = {13}, - abstract = {How neuronal diversity emerges from complex patterns of gene expression remains poorly understood. Here we present an approach to understand electrophysiological diversity through gene expression by integrating pooled- and single-cell transcriptomics with intracellular electrophysiology. Using neuroinformatics methods, we compiled a brain-wide dataset of 34 neuron types with paired gene expression and intrinsic electrophysiological features from publically accessible sources, the largest such collection to date. We identified 420 genes whose expression levels significantly correlated with variability in one or more of 11 physiological parameters. We next trained statistical models to infer cellular features from multivariate gene expression patterns. Such models were predictive of gene-electrophysiological relationships in an independent collection of 12 visual cortex cell types from the Allen Institute, suggesting that these correlations might reflect general principles relating expression patterns to phenotypic diversity across very different cell types. Many associations reported here have the potential to provide new insights into how neurons generate functional diversity, and correlations of ion channel genes like Gabrd and Scn1a (Nav1.1) with resting potential and spiking frequency are consistent with known causal mechanisms. Our work highlights the promise and inherent challenges in using cell type-specific transcriptomics to understand the mechanistic origins of neuronal diversity.}, - doi = {10.1371/journal.pcbi.1005814}, - file = {:Tripathy2017 - Transcriptomic Correlates of Neuron Electrophysiological Diversity.pdf:PDF}, - keywords = {Gene expression, Electrophysiology, Transcriptome analysis, Brain electrophysiology, Neurons, Action potentials, Ion channels, Electrophysiological properties}, - language = {english}, - publisher = {Public Library of Science}, - -} - - -@Book{Izhikevich2006, - author = {Izhikevich, Eugene M.}, - editor = {Sejnowski, Terrence J. and Poggio, Tomaso A.}, - publisher = {MIT Press}, - title = {Dynamical {Systems} in {Neuroscience}: {The} {Geometry} of {Excitability} and {Bursting}}, - year = {2006}, - address = {Cambridge, MA, USA}, - isbn = {9780262090438}, - month = jul, - series = {Computational {Neuroscience} {Series}}, - abstract = {Explains the relationship of electrophysiology, nonlinear dynamics, and the computational properties of neurons, with each concept presented in terms of both neuroscience and mathematics and illustrated using geometrical intuition.}, - language = {english}, - shorttitle = {Dynamical {Systems} in {Neuroscience}}, -} - - -@Article{Wolff2017, - author = {Wolff, Markus and others}, - journal = {Brain}, - title = {Genetic and phenotypic heterogeneity suggest therapeutic implications in {SCN2A}-related disorders}, - year = {2017}, - issn = {0006-8950}, - month = may, - number = {5}, - pages = {1316--1336}, - volume = {140}, - abstract = {Mutations in SCN2A, a gene encoding the voltage-gated sodium channel Nav1.2, have been associated with a spectrum of epilepsies and neurodevelopmental disorders. Here, we report the phenotypes of 71 patients and review 130 previously reported patients. We found that (i) encephalopathies with infantile/childhood onset epilepsies (≥3 months of age) occur almost as often as those with an early infantile onset (\<3 months), and are thus more frequent than previously reported; (ii) distinct phenotypes can be seen within the late onset group, including myoclonic-atonic epilepsy (two patients), Lennox-Gastaut not emerging from West syndrome (two patients), and focal epilepsies with an electrical status epilepticus during slow sleep-like EEG pattern (six patients); and (iii) West syndrome constitutes a common phenotype with a major recurring mutation (p.Arg853Gln: two new and four previously reported children). Other known phenotypes include Ohtahara syndrome, epilepsy of infancy with migrating focal seizures, and intellectual disability or autism without epilepsy. To assess the response to antiepileptic therapy, we retrospectively reviewed the treatment regimen and the course of the epilepsy in 66 patients for which well-documented medical information was available. We find that the use of sodium channel blockers was often associated with clinically relevant seizure reduction or seizure freedom in children with early infantile epilepsies (\<3 months), whereas other antiepileptic drugs were less effective. In contrast, sodium channel blockers were rarely effective in epilepsies with later onset (≥3 months) and sometimes induced seizure worsening. Regarding the genetic findings, truncating mutations were exclusively seen in patients with late onset epilepsies and lack of response to sodium channel blockers. Functional characterization of four selected missense mutations using whole cell patch-clamping in tsA201 cells—together with data from the literature—suggest that mutations associated with early infantile epilepsy result in increased sodium channel activity with gain-of-function, characterized by slowing of fast inactivation, acceleration of its recovery or increased persistent sodium current. Further, a good response to sodium channel blockers clinically was found to be associated with a relatively small gain-of-function. In contrast, mutations in patients with late-onset forms and an insufficient response to sodium channel blockers were associated with loss-of-function effects, including a depolarizing shift of voltage-dependent activation or a hyperpolarizing shift of channel availability (steady-state inactivation). Our clinical and experimental data suggest a correlation between age at disease onset, response to sodium channel blockers and the functional properties of mutations in children with SCN2A-related epilepsy.}, - doi = {10.1093/brain/awx054}, - file = {:wolff_genetic_2017 - Genetic and Phenotypic Heterogeneity Suggest Therapeutic Implications in SCN2A Related Disorders.pdf:PDF}, -} - - -@Article{Wei2017, - author = {Wei, Feng and Yan, Li-Min and Su, Tao and He, Na and Lin, Zhi-Jian and Wang, Jie and Shi, Yi-Wu and Yi, Yong-Hong and Liao, Wei-Ping}, - journal = {Neuroscience Bulletin}, - title = {Ion {Channel} {Genes} and {Epilepsy}: {Functional} {Alteration}, {Pathogenic} {Potential}, and {Mechanism} of {Epilepsy}}, - year = {2017}, - issn = {1673-7067}, - month = may, - number = {4}, - pages = {455--477}, - volume = {33}, - abstract = {Ion channels are crucial in the generation and modulation of excitability in the nervous system and have been implicated in human epilepsy. Forty-one epilepsy-associated ion channel genes and their mutations are systematically reviewed. In this paper, we analyzed the genotypes, functional alterations (funotypes), and phenotypes of these mutations. Eleven genes featured loss-of-function mutations and six had gain-of-function mutations. Nine genes displayed diversified funotypes, among which a distinct funotype-phenotype correlation was found in SCN1A. These data suggest that the funotype is an essential consideration in evaluating the pathogenicity of mutations and a distinct funotype or funotype-phenotype correlation helps to define the pathogenic potential of a gene.}, - doi = {10.1007/s12264-017-0134-1}, - pmcid = {PMC5567559}, - pmid = {28488083}, - shorttitle = {Ion {Channel} {Genes} and {Epilepsy}}, - urldate = {2022-05-16}, -} - - -@Article{Kim2021, - author = {Kim, Hyo Jeong and Kang, Hoon-Chul}, - title = {Treatment strategies targeting specific genetic etiologies in epilepsy}, - year = {2021}, - issn = {1226-1769}, - month = jun, - number = {1}, - pages = {8--15}, - volume = {18}, - abstract = {Hyo Jeong Kim and Hoon-Chul Kang. J Genet Med 2021;18:8-15. https://doi.org/10.5734/JGM.2021.18.1.8}, - doi = {10.5734/JGM.2021.18.1.8}, - language = {english}, - publisher = {Korean Society of Medical Genetics and Genomics}, - urldate = {2022-05-16}, -} - - -@Article{BICCN2021, - author = {{BRAIN Initiative Cell Census Network}}, - journal = {Nature}, - title = {A multimodal cell census and atlas of the mammalian primary motor cortex}, - year = {2021}, - issn = {0028-0836}, - number = {7879}, - pages = {86--102}, - volume = {598}, - abstract = {Here we report the generation of a multimodal cell census and atlas of the mammalian primary motor cortex as the initial product of the BRAIN Initiative Cell Census Network (BICCN). This was achieved by coordinated large-scale analyses of single-cell transcriptomes, chromatin accessibility, DNA methylomes, spatially resolved single-cell transcriptomes, morphological and electrophysiological properties and cellular resolution input–output mapping, integrated through cross-modal computational analysis. Our results advance the collective knowledge and understanding of brain cell-type organization–. First, our study reveals a unified molecular genetic landscape of cortical cell types that integrates their transcriptome, open chromatin and DNA methylation maps. Second, cross-species analysis achieves a consensus taxonomy of transcriptomic types and their hierarchical organization that is conserved from mouse to marmoset and human. Third, in situ single-cell transcriptomics provides a spatially resolved cell-type atlas of the motor cortex. Fourth, cross-modal analysis provides compelling evidence for the transcriptomic, epigenomic and gene regulatory basis of neuronal phenotypes such as their physiological and anatomical properties, demonstrating the biological validity and genomic underpinning of neuron types. We further present an extensive genetic toolset for targeting glutamatergic neuron types towards linking their molecular and developmental identity to their circuit function. Together, our results establish a unifying and mechanistic framework of neuronal cell-type organization that integrates multi-layered molecular genetic and spatial information with multi-faceted phenotypic properties., The BRAIN Initiative Cell Census Network has constructed a multimodal cell census and atlas of the mammalian primary motor cortex in a landmark effort towards understanding brain cell-type diversity, neural circuit organization and brain function.}, - doi = {10.1038/s41586-021-03950-0}, - pmcid = {PMC8494634}, - pmid = {34616075}, - urldate = {2022-05-06}, -} - - -@Article{Layer2021, - author = {Layer, Nikolas and Sonnenberg, Lukas and Pardo González, Emilio and Benda, Jan and Hedrich, Ulrike B. S. and Lerche, Holger and Koch, Henner and Wuttke, Thomas V.}, - journal = {Frontiers in Cellular Neuroscience}, - title = {Dravet {Variant} {SCN1AA1783V} {Impairs} {Interneuron} {Firing} {Predominantly} by {Altered} {Channel} {Activation}}, - year = {2021}, - issn = {1662-5102}, - volume = {15}, - abstract = {Dravet syndrome (DS) is a developmental epileptic encephalopathy mainly caused by functional NaV1.1 haploinsufficiency in inhibitory interneurons. Recently, a new conditional mouse model expressing the recurrent human p.(Ala1783Val) missense variant has become available. In this study, we provided an electrophysiological characterization of this variant in tsA201 cells, revealing both altered voltage-dependence of activation and slow inactivation without reduced sodium peak current density. Based on these data, simulated interneuron (IN) firing properties in a conductance-based single-compartment model suggested surprisingly similar firing deficits for NaV1.1A1783V and full haploinsufficiency as caused by heterozygous truncation variants. Impaired NaV1.1A1783V channel activation was predicted to have a significantly larger impact on channel function than altered slow inactivation and is therefore proposed as the main mechanism underlying IN dysfunction. The computational model was validated in cortical organotypic slice cultures derived from conditional Scn1aA1783V mice. Pan-neuronal activation of the p.Ala1783V in vitro confirmed a predicted IN firing deficit and revealed an accompanying reduction of interneuronal input resistance while demonstrating normal excitability of pyramidal neurons. Altered input resistance was fed back into the model for further refinement. Taken together these data demonstrate that primary loss of function (LOF) gating properties accompanied by altered membrane characteristics may match effects of full haploinsufficiency on the neuronal level despite maintaining physiological peak current density, thereby causing DS.}, - doi = {10.3389/fncel.2021.754530}, - urldate = {2022-04-27}, -} - -@Article{Noebels2017, - author = {Noebels, Jeffrey}, - journal = {The Journal of General Physiology}, - title = {Precision physiology and rescue of brain ion channel disorders}, - year = {2017}, - issn = {0022-1295}, - month = may, - number = {5}, - pages = {533--546}, - volume = {149}, - abstract = {Noebels highlights the importance of cellular and circuit-level context for understanding channelopathies of the brain., Ion channel genes, originally implicated in inherited excitability disorders of muscle and heart, have captured a major role in the molecular diagnosis of central nervous system disease. Their arrival is heralded by neurologists confounded by a broad phenotypic spectrum of early-onset epilepsy, autism, and cognitive impairment with few effective treatments. As detection of rare structural variants in channel subunit proteins becomes routine, it is apparent that primary sequence alone cannot reliably predict clinical severity or pinpoint a therapeutic solution. Future gains in the clinical utility of variants as biomarkers integral to clinical decision making and drug discovery depend on our ability to unravel complex developmental relationships bridging single ion channel structure and human physiology.}, - doi = {10.1085/jgp.201711759}, - pmcid = {PMC5412535}, - pmid = {28428202}, - urldate = {2022-04-13}, -} - - -@Article{Dunlop2008, - author = {Dunlop, John and Bowlby, Mark and Peri, Ravikumar and Vasilyev, Dmytro and Arias, Robert}, - journal = {Nature Reviews Drug Discovery}, - title = {High-throughput electrophysiology: an emerging paradigm for ion-channel screening and physiology}, - year = {2008}, - issn = {1474-1784}, - month = apr, - number = {4}, - pages = {358--368}, - volume = {7}, - abstract = {Ion channels represent an important class of druggable targets; however, it is generally appreciated in the field that ion-channel targeted drug discovery has been hampered by the unavailability of high-throughput platforms that use electrophysiological techniques for the characterization of compound activity. To address this bottleneck, in the past 5 years, several companies have developed and introduced automated platforms for performing electrophysiological studies.This recent explosion includes different approaches taken to carry out multi-channel planar-array based patch-clamp recordings of mammalian cells, resulting in the commercialization of four systems — IonWorks, PatchXpress, Patchliner and CytoPatch. Complementary to these technologies has been the development of lower capacity systems that fully automate conventional manual patch-clamp recordings including the Flyscreen, AutoPatch and RoboPatch for mammalian cells, and the Robocyte and OpusXpress 6000A for Xenopus oocytes.Despite the sophisticated technologies that are now available, automating patch-clamp electrophysiology often presents underestimated challenges regarding reproducibility with the cells being used; this needs to be fully appreciated when embarking on the implementation of any of these approaches.The need to assess the potential of drug candidates to inhibit cardiac ion-channels, particularly hERG, has greatly contributed to the development of these technologies. Although higher throughput non-electrophysiological assays have a reasonable predictive potential, they have several limitations that might be technically or chemically limiting. Consequently, the desire to use electrophysiological assays early on to assess ion-channel liabilities has been one of the key drivers for implementation of automated electrophysiology.Compound screening against molecularly isolated, heterologously expressed ion channels, will often identify drug candidates whose higher-order impact on networked neuronal systems are not necessarily inferable from their effects on individual conductances. Raising the throughput of pharmacological evaluation in such higher-order systems presents a distinct set of challenges. However, recent progress has been made in the development of automated systems for performing electrophysiogical studies in brain slices and other intact biological preparations.The availability of these technologies has re-energized ion-channel targeted drug discovery by allowing the development of screening paradigms that were not feasible in the pre-automation era. In our opinion this holds much promise for the discovery and development of innovative new ion-channel targeted drugs. Tractability of ion channels as drug targets coupled with future advances in technology platforms and decreased cost of consumables are expected to support an even wider implementation of these automated systems.}, - copyright = {2008 Nature Publishing Group}, - doi = {10.1038/nrd2552}, - keywords = {Biomedicine, general, Pharmacology/Toxicology, Biotechnology, Medicinal Chemistry, Molecular Medicine, Cancer Research}, - language = {english}, - publisher = {Nature Publishing Group}, - shorttitle = {High-throughput electrophysiology}, - urldate = {2022-04-13}, -} - -@Article{Balestrini1044, - author = {Balestrini, Simona and others}, - journal = {Journal of Neurology, Neurosurgery \& Psychiatry}, - title = {Real-life survey of pitfalls and successes of precision medicine in genetic epilepsies}, - year = {2021}, - issn = {0022-3050}, - number = {10}, - pages = {1044--1052}, - volume = {92}, - abstract = {Objective The term {\textquoteleft}precision medicine{\textquoteright} describes a rational treatment strategy tailored to one person that reverses or modifies the disease pathophysiology. In epilepsy, single case and small cohort reports document nascent precision medicine strategies in specific genetic epilepsies. The aim of this multicentre observational study was to investigate the deeper complexity of precision medicine in epilepsy.Methods A systematic survey of patients with epilepsy with a molecular genetic diagnosis was conducted in six tertiary epilepsy centres including children and adults. A standardised questionnaire was used for data collection, including genetic findings and impact on clinical and therapeutic management.Results We included 293 patients with genetic epilepsies, 137 children and 156 adults, 162 females and 131 males. Treatment changes were undertaken because of the genetic findings in 94 patients (32\%), including rational precision medicine treatment and/or a treatment change prompted by the genetic diagnosis, but not directly related to known pathophysiological mechanisms. There was a rational precision medicine treatment for 56 patients (19\%), and this was tried in 33/56 (59\%) and was successful (ie, \>50\% seizure reduction) in 10/33 (30\%) patients. In 73/293 (25\%) patients there was a treatment change prompted by the genetic diagnosis, but not directly related to known pathophysiological mechanisms, and this was successful in 24/73 (33\%).Significance Our survey of clinical practice in specialised epilepsy centres shows high variability of clinical outcomes following the identification of a genetic cause for an epilepsy. Meaningful change in the treatment paradigm after genetic testing is not yet possible for many people with epilepsy. This systematic survey provides an overview of the current application of precision medicine in the epilepsies, and suggests the adoption of a more considered approach.Data are available on reasonable request. The authors confirm that the data supporting the findings of this study are available from the corresponding author, on reasonable request and subject to protocol approvals at each contributing site.}, - doi = {10.1136/jnnp-2020-325932}, - eprint = {https://jnnp.bmj.com/content/92/10/1044.full.pdf}, - publisher = {BMJ Publishing Group Ltd}, -} - -@Article{chi_manipulation_2007, - author = {Chi, Xian Xuan and Nicol, G. D.}, - journal = {Journal of Neurophysiology}, - title = {Manipulation of the {Potassium} {Channel} {Kv1}.1 and {Its} {Effect} on {Neuronal} {Excitability} in {Rat} {Sensory} {Neurons}}, - year = {2007}, - issn = {0022-3077}, - month = nov, - number = {5}, - pages = {2683--2692}, - volume = {98}, - abstract = {Potassium channels play a critical role in regulating many aspects of action potential (AP) firing. To establish the contribution of the voltage-dependent potassium channel Kv1.1 in regulating excitability, we used the selective blocker dendrotoxin-K (DTX-K) and small interfering RNA (siRNA) targeted to Kv1.1 to determine their effects on AP firing in small-diameter capsaicin-sensitive sensory neurons. A 5-min exposure to 10 nM DTX-K suppressed the total potassium current (IK) measured at +40 mV by about 33\%. DTX-K produced a twofold increase in the number of APs evoked by a ramp of depolarizing current. Associated with increased firing was a decrease in firing threshold and rheobase. DTX-K did not alter the resting membrane potential or the AP duration. A 48-h treatment with siRNA targeted to Kv1.1 reduced the expression of this channel protein by about 60\% as measured in Western blots. After treatment with siRNA, IK was no longer sensitive to DTX-K, indicating a loss of functional protein. Similarly, after siRNA treatment exposure to DTX-K had no effect on the number of evoked APs, firing threshold, or rheobase. However, after siRNA treatment, the firing threshold had values similar to those obtained after acute exposure to DTX-K, suggesting that the loss of Kv1.1 plays a critical role in setting this parameter of excitability. These results demonstrate that Kv1.1 plays an important role in limiting AP firing and that siRNA may be a useful approach to establish the role of specific ion channels in the absence of selective antagonists.}, - doi = {10.1152/jn.00437.2007}, - file = {Full Text PDF:C\:/Users/nilsk/Zotero/storage/4K5J2PLY/Chi and Nicol - 2007 - Manipulation of the Potassium Channel Kv1.1 and It.pdf:application/pdf;Snapshot:C\:/Users/nilsk/Zotero/storage/K6U2R6HN/jn.00437.html:text/html}, - urldate = {2021-06-10}, -} - - - -@Article{johannesen_genotype-phenotype_2021, - author = {Johannesen, Katrine M. and others}, - journal = {medRxiv}, - title = {Genotype-phenotype correlations in {SCN8A}-related disorders reveal prognostic and therapeutic implications}, - year = {2021}, - month = mar, - pages = {2021.03.22.21253711}, - abstract = {{\textless}h3{\textgreater}Abstract{\textless}/h3{\textgreater} {\textless}p{\textgreater}We report detailed functional analyses and genotype-phenotype correlations in 433 individuals carrying disease-causing variants in \textit{SCN8A}, encoding the voltage-gated Na$^{\textrm{+}}$ channel Na$_{\textrm{V}}$1.6. Five different clinical subgroups could be identified: 1) Benign familial infantile epilepsy (BFIE) (n=17, normal cognition, treatable seizures), 2) intermediate epilepsy (n=36, mild ID, partially pharmacoresponsive), 3) developmental and epileptic encephalopathy (DEE, n=191, severe ID, majority pharmacoresistant), 4) generalized epilepsy (n=21, mild to moderate ID, frequently with absence seizures), and 5) affected individuals without epilepsy (n=25, mild to moderate ID). Groups 1-3 presented with early-onset (median: four months) focal or multifocal seizures and epileptic discharges, whereas the onset of seizures in group 4 was later (median: 39 months) with generalized epileptic discharges. The epilepsy was not classifiable in 143 individuals. We performed functional studies expressing missense variants in ND7/23 neuroblastoma cells and primary neuronal cultures using recombinant tetrodotoxin insensitive human Na$_{\textrm{V}}$1.6 channels and whole-cell patch clamping. Two variants causing DEE showed a strong gain-of-function (GOF, hyperpolarising shift of steady-state activation, strongly increased neuronal firing rate), and one variant causing BFIE or intermediate epilepsy showed a mild GOF (defective fast inactivation, less increased firing). In contrast, all three variants causing generalized epilepsy induced a loss-of-function (LOF, reduced current amplitudes, depolarising shift of steady-state activation, reduced neuronal firing). Including previous studies, functional effects were known for 165 individuals. All 133 individuals carrying GOF variants had either focal (76, groups 1-3), or unclassifiable epilepsy (37), whereas 32 with LOF variants had either generalized (14), no (11) or unclassifiable (5) epilepsy; only two had DEE. Computational modeling in the GOF group revealed a significant correlation between the severity of the electrophysiological and clinical phenotypes. GOF variant carriers responded significantly better to sodium channel blockers (SCBs) than to other anti-seizure medications, and the same applied for all individuals of groups 1-3.{\textless}/p{\textgreater}{\textless}p{\textgreater}In conclusion, our data reveal clear genotype-phenotype correlations between age at seizure onset, type of epilepsy and gain- or loss-of-function effects of \textit{SCN8A} variants. Generalized epilepsy with absence seizures is the main epilepsy phenotype of LOF variant carriers and the extent of the electrophysiological dysfunction of the GOF variants is a main determinant of the severity of the clinical phenotype in focal epilepsies. Our pharmacological data indicate that SCBs present a therapeutic treatment option in early onset \textit{SCN8A}-related focal epilepsy.{\textless}/p{\textgreater}}, - copyright = {© 2021, Posted by Cold Spring Harbor Laboratory. This pre-print is available under a Creative Commons License (Attribution-NoDerivs 4.0 International), CC BY-ND 4.0, as described at http://creativecommons.org/licenses/by-nd/4.0/}, - doi = {10.1101/2021.03.22.21253711}, - file = {Full Text PDF:C\:/Users/nilsk/Zotero/storage/473Q4W4Z/Johannesen et al. - 2021 - Genotype-phenotype correlations in SCN8A-related d.pdf:application/pdf;Full Text PDF:C\:/Users/nilsk/Zotero/storage/I4ATHYDV/Johannesen et al. - 2021 - Genotype-phenotype correlations in SCN8A-related d.pdf:application/pdf;Full Text PDF:C\:/Users/nilsk/Zotero/storage/5BLXZ69T/Johannesen et al. - 2021 - Genotype-phenotype correlations in SCN8A-related d.pdf:application/pdf;Snapshot:C\:/Users/nilsk/Zotero/storage/4UWL4V5H/2021.03.22.html:text/html;Snapshot:C\:/Users/nilsk/Zotero/storage/E7KCJBEZ/2021.03.22.html:text/html;Snapshot:C\:/Users/nilsk/Zotero/storage/FS6JAG82/2021.03.22.html:text/html}, - language = {english}, - urldate = {2021-07-29}, -} - - -@Article{smart_deletion_1998, - author = {Smart, Sharon L. and Lopantsev, Valeri and Zhang, C. L. and Robbins, Carol A. and Wang, Hao and Chiu, S. Y. and Schwartzkroin, Philip A. and Messing, Albee and Tempel, Bruce L.}, - journal = {Neuron}, - title = {Deletion of the {KV1}.1 {Potassium} {Channel} {Causes} {Epilepsy} in {Mice}}, - year = {1998}, - issn = {0896-6273}, - month = apr, - number = {4}, - pages = {809--819}, - volume = {20}, - abstract = {Mice lacking the voltage-gated potassium channel α subunit, KV1.1, display frequent spontaneous seizures throughout adult life. In hippocampal slices from homozygous KV1.1 null animals, intrinsic passive properties of CA3 pyramidal cells are normal. However, antidromic action potentials are recruited at lower thresholds in KV1.1 null slices. Furthermore, in a subset of slices, mossy fiber stimulation triggers synaptically mediated long-latency epileptiform burst discharges. These data indicate that loss of KV1.1 from its normal localization in axons and terminals of the CA3 region results in increased excitability in the CA3 recurrent axon collateral system, perhaps contributing to the limbic and tonic–clonic components of the observed epileptic phenotype. Axonal action potential conduction was altered as well in the sciatic nerve—a deficit potentially related to the pathophysiology of episodic ataxia/myokymia, a disease associated with missense mutations of the human KV1.1 gene.}, - doi = {10.1016/S0896-6273(00)81018-1}, - file = {ScienceDirect Full Text PDF:C\:/Users/nilsk/Zotero/storage/BWWW4ZL8/Smart et al. - 1998 - Deletion of the KV1.1 Potassium Channel Causes Epi.pdf:application/pdf;ScienceDirect Snapshot:C\:/Users/nilsk/Zotero/storage/A7QYCC6F/S0896627300810181.html:text/html}, - language = {english}, - urldate = {2021-06-10}, -} - -@Article{wang__1999, - author = {Wang, Fan C. and Parcej, David N. and Dolly, J. Oliver}, - journal = {European Journal of Biochemistry}, - title = {α {Subunit} compositions of {Kv1}.1-containing {K}+ channel subtypes fractionated from rat brain using dendrotoxins}, - year = {1999}, - issn = {1432-1033}, - number = {1}, - pages = {230--237}, - volume = {263}, - abstract = {K+ channels from the Kv1 subfamily contain four α-subunits and the combinations (from Kv1.1–1.6) determine susceptibility to dendrotoxin (DTX) homologues. The subunit composition of certain subtypes in rat brain was investigated using DTXk which only interacts with Kv1.1-containing channels and αDTX (and its closely related homologue DTXi) that binds preferentially to Kv1.2-possessing homo- or hetero-oligomers. Covalent attachment of [125I]DTXk bound to channels in synaptic membranes unveiled subunits of Mr = 78 000 and 96 000. Immunoprecipitation of these solubilized and dissociated cross-linked proteins with IgG specific for each of the α-subunits identified Kv1.1, 1.2 and 1.4; this led to assemblies of Kv1.1/1.2 and 1.1/1.4 being established. Kv1.2-enriched channels, purified from rat brain by chromatography on immobilized DTXi, contained Kv1.1, 1.2 and 1.6 confirming one of the above-noted pairs and indicating an additional Kv1.1-containing oligomer (Kv1.1/1.2/1.6); the notable lack of Kv1.4 excludes a Kv1.1/1.2/1.4 combination. On the other hand, channels with Kv1.1 as a constituent, isolated using DTXk, possessed Kv1.4 in addition to those found in the DTXi-purified oligomers; this provides convergent support for the occurrence of the three combinations established above but adds a possible fourth (Kv1.1/1.4/1.6), though this was not confirmed. Moreover, sequential purification on DTXi and DTXk resins yielded channels containing only Kv1.1/1.2 but with an apparent predominance of Kv1.1, reaffirming the latter multimer.}, - doi = {10.1046/j.1432-1327.1999.00493.x}, - file = {Full Text PDF:C\:/Users/nilsk/Zotero/storage/UZDUM8RP/Wang et al. - 1999 - α Subunit compositions of Kv1.1-containing K+ chan.pdf:application/pdf;Snapshot:C\:/Users/nilsk/Zotero/storage/99X9K88C/j.1432-1327.1999.00493.html:text/html}, - keywords = {K+ channels, dendrotoxins., hetero-oligomers, voltage-gated, α and β subunits}, - language = {english}, - urldate = {2021-06-07}, -} - - -@Article{Smith2018, - author = {Smith, Richard S. and others}, - journal = {Neuron}, - title = {Sodium {Channel} {SCN3A} ({NaV1}.3) {Regulation} of {Human} {Cerebral} {Cortical} {Folding} and {Oral} {Motor} {Development}}, - year = {2018}, - issn = {0896-6273}, - month = sep, - number = {5}, - pages = {905--913.e7}, - volume = {99}, - abstract = {Channelopathies are disorders caused by abnormal ion channel function in differentiated excitable tissues. We discovered a unique neurodevelopmental channelopathy resulting from pathogenic variants in SCN3A, a gene encoding the voltage-gated sodium channel NaV1.3. Pathogenic NaV1.3 channels showed altered biophysical properties including increased persistent current. Remarkably, affected individuals showed disrupted folding (polymicrogyria) of the perisylvian cortex of the brain but did not typically exhibit epilepsy; they presented with prominent speech and oral motor dysfunction, implicating SCN3A in prenatal development of human cortical language areas. The development of this disorder parallels SCN3A expression, which we observed to be highest early in fetal cortical development in progenitor cells of the outer subventricular zone and cortical plate neurons and decreased postnatally, when SCN1A (NaV1.1) expression increased. Disrupted cerebral cortical folding and neuronal migration were recapitulated in ferrets expressing the mutant channel, underscoring the unexpected role of SCN3A in progenitor cells and migrating neurons.}, - doi = {10.1016/j.neuron.2018.07.052}, - groups = {Jan}, - keywords = {Cortical Development, Polymicrogyria, Oromotor, Speech, Na1.3, Na1.1, Voltage-Gated Sodium Channel (VGSC), Outer Radial Glia}, - language = {english}, - urldate = {2022-04-03}, -} - -@Article{golowasch_failure_2002, - author = {Golowasch, Jorge and Goldman, Mark S. and Abbott, L. F. and Marder, Eve}, - journal = {Journal of Neurophysiology}, - title = {Failure of {Averaging} in the {Construction} of a {Conductance}-{Based} {Neuron} {Model}}, - year = {2002}, - issn = {0022-3077}, - month = feb, - number = {2}, - pages = {1129--1131}, - volume = {87}, - abstract = {Parameters for models of biological systems are often obtained by averaging over experimental results from a number of different preparations. To explore the validity of this procedure, we studied the behavior of a conductance-based model neuron with five voltage-dependent conductances. We randomly varied the maximal conductance of each of the active currents in the model and identified sets of maximal conductances that generate bursting neurons that fire a single action potential at the peak of a slow membrane potential depolarization. A model constructed using the means of the maximal conductances of this population is not itself a one-spike burster, but rather fires three action potentials per burst. Averaging fails because the maximal conductances of the population of one-spike bursters lie in a highly concave region of parameter space that does not contain its mean. This demonstrates that averages over multiple samples can fail to characterize a system whose behavior depends on interactions involving a number of highly variable components.}, - doi = {10.1152/jn.00412.2001}, - file = {Full Text PDF:C\:/Users/nilsk/Zotero/storage/3XUIS8H6/Golowasch et al. - 2002 - Failure of Averaging in the Construction of a Cond.pdf:application/pdf;Snapshot:C\:/Users/nilsk/Zotero/storage/3PM5WXVV/jn.00412.html:text/html}, - urldate = {2021-06-17}, -} - -@Article{lamb_correlated_2013, - author = {Lamb, Damon G. and Calabrese, Ronald L.}, - journal = {PLOS ONE}, - title = {Correlated {Conductance} {Parameters} in {Leech} {Heart} {Motor} {Neurons} {Contribute} to {Motor} {Pattern} {Formation}}, - year = {2013}, - issn = {1932-6203}, - month = nov, - number = {11}, - pages = {e79267}, - volume = {8}, - abstract = {Neurons can have widely differing intrinsic membrane properties, in particular the density of specific conductances, but how these contribute to characteristic neuronal activity or pattern formation is not well understood. To explore the relationship between conductances, and in particular how they influence the activity of motor neurons in the well characterized leech heartbeat system, we developed a new multi-compartmental Hodgkin-Huxley style leech heart motor neuron model. To do so, we evolved a population of model instances, which differed in the density of specific conductances, capable of achieving specific output activity targets given an associated input pattern. We then examined the sensitivity of measures of output activity to conductances and how the model instances responded to hyperpolarizing current injections. We found that the strengths of many conductances, including those with differing dynamics, had strong partial correlations and that these relationships appeared to be linked by their influence on heart motor neuron activity. Conductances that had positive correlations opposed one another and had the opposite effects on activity metrics when perturbed whereas conductances that had negative correlations could compensate for one another and had similar effects on activity metrics.}, - doi = {10.1371/journal.pone.0079267}, - file = {Full Text PDF:C\:/Users/nilsk/Zotero/storage/L77ATPCI/Lamb and Calabrese - 2013 - Correlated Conductance Parameters in Leech Heart M.pdf:application/pdf;Snapshot:C\:/Users/nilsk/Zotero/storage/V74V8IWQ/article.html:text/html}, - keywords = {Interneurons, Motor neurons, Action potentials, Membrane potential, Axons, Heart, Leeches, Neurites}, - language = {english}, - urldate = {2021-07-01}, -} - -@Article{morales-villagran_protection_1996, - author = {Morales-Villagrán, Alberto and Ureña-Guerrero, Mónica E. and Tapia, Ricardo}, - journal = {European Journal of Pharmacology}, - title = {Protection by {NMDA} receptor antagonists against seizures induced by intracerebral administration of 4-aminopyridine}, - year = {1996}, - issn = {0014-2999}, - month = jun, - number = {1}, - pages = {87--93}, - volume = {305}, - abstract = {The effects of NMDA receptor antagonists on the convulsant action of the administration of 4-aminopyridine in the rat lateral cerebral ventricle (i.c.v. injection) and motor cerebral cortex (i.cx. injection) were studied. 4-Aminopyridine administration in both regions induced various preconvulsive symptoms, such as salivation, tremors, chewing and rearing, followed by continuous clonic convulsions and, only after i.c.v. injection, running fits and generalized tonic convulsions. This behavioral pattern appeared 5–9 min after administration of 4-aminopyridine and persisted for 100–150 min. 4-Aminopyridine also generated epileptiform electroencephalographic (EEG) discharges characterized by isolated spikes, poly-spikes and spike-wave complexes, which began some seconds after administration of the drug and were present for more than 2 h. The NMDA receptor antagonists (±)-3-(2-carboxy-piperazin-4-yl)-propyl-1-phosphonic acid (CPP), (±)-2-amino-7-phosphono-heptanoic acid (AP7) and (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate (MK-801) clearly protected against some of the behavioral alterations induced by i.c.v. 4-aminopyridine, particularly the tonic convulsions, but were less effective against those produced by i.cx. 4-aminopyridine. These antagonists also delayed the appearance of EEG epileptiform discharges, reduced its amplitude, frequency and duration, and blocked their propagation to other cortical regions after i.cx. 4-aminopyridine. These results, together with previous data showing that 4-aminopyridine stimulates the release of glutamate in vivo, suggest that an excessive glutamatergic neurotransmission involving NMDA receptors is implicated in 4-aminopyridine-induced seizures.}, - doi = {10.1016/0014-2999(96)00157-4}, - file = {ScienceDirect Full Text PDF:C\:/Users/nilsk/Zotero/storage/CIJQBWZV/Morales-Villagrán et al. - 1996 - Protection by NMDA receptor antagonists against se.pdf:application/pdf;ScienceDirect Snapshot:C\:/Users/nilsk/Zotero/storage/9EDF8NNK/0014299996001574.html:text/html}, - keywords = {Seizure, 4-Aminopyridine, Excitatory amino acid neurotransmission, NMDA receptor antagonist}, - language = {english}, - urldate = {2021-06-12}, -} - -@Article{graves_episodic_2014, - author = {Graves, Tracey D. and Cha, Yoon-Hee and Hahn, Angelika F. and Barohn, Richard and Salajegheh, Mohammed K. and Griggs, Robert C. and Bundy, Brian N. and Jen, Joanna C. and Baloh, Robert W. and Hanna, Michael G. and {on behalf of the CINCH Investigators}}, - journal = {Brain}, - title = {Episodic ataxia type 1: clinical characterization, quality of life and genotype–phenotype correlation}, - year = {2014}, - issn = {0006-8950}, - month = apr, - number = {4}, - pages = {1009--1018}, - volume = {137}, - abstract = {Episodic ataxia type 1 is considered a rare neuronal ion channel disorder characterized by brief attacks of unsteadiness and dizziness with persistent myokymia. To characterize the natural history, develop outcome measures for future clinical trials, and correlate genotype with phenotype, we undertook an international, prospective, cross-sectional study. Thirty-nine individuals (51\% male) were enrolled: median age 37 years (range 15–65 years). We identified 10 different pathogenic point mutations in KCNA1 that accounted for the genetic basis of 85\% of the cohort. Participants with KCNA1 mutations were more likely to have a positive family history. Analysis of the total cohort showed that the first episode of ataxia occurred before age 20 in all but one patient, with an average age of onset of 7.9 years. Physical exertion, emotional stress and environmental temperature were the most common triggers for attacks. Attack frequency ranged from daily to monthly, even with the same KCNA1 genotype. Average attack duration was in the order of minutes. Ten participants (26\%) developed permanent cerebellar signs, which were related to disease duration. The average Scale for the Assessment and Rating of Ataxia score (SARA, a standardized measure of cerebellar dysfunction on clinical examination, scores range from 0–40) was an average of 3.15 for all participants (range 0–14), but was only 2 in those with isolated episodic ataxia compared with 7.7 in those with progressive cerebellar ataxia in addition to episodic ataxia. Thirty-seven participants completed the SF-36, a quality of life survey; all eight domain norm-based average scores (mean = 50) were below normal with mental health being the lowest (41.3) in those with mutation positive episodic ataxia type 1. Scores on SF-36 correlated negatively with attack frequency. Of the 39 participants in the study, 33 harboured mutations in KCNA1 whereas the remaining six had no mutation identified. Episodic ataxia type 1 phenocopies have not been described previously and we report their clinical features, which appear to be different to those with a KCNA1 mutation. This large prospective study of both genetically confirmed episodic ataxia type 1 and episodic ataxia type 1 phenocopies provides detailed baseline characteristics of these disorders and their impact on participants. We found that attacks had a significant effect on quality of life. Unlike previous studies, we found that a significant number of individuals with genetically confirmed episodic ataxia type 1 (21\%) had accumulated persistent cerebellar symptoms and signs. These data will enable the development of outcome measures for clinical trials of treatment.}, - doi = {10.1093/brain/awu012}, - file = {Full Text PDF:C\:/Users/nilsk/Zotero/storage/GW4CYP4I/Graves et al. - 2014 - Episodic ataxia type 1 clinical characterization,.pdf:application/pdf;Full Text PDF:C\:/Users/nilsk/Zotero/storage/962LHS6A/Graves et al. - 2014 - Episodic ataxia type 1 clinical characterization,.pdf:application/pdf;Snapshot:C\:/Users/nilsk/Zotero/storage/G5KRDWAE/367720.html:text/html;Snapshot:C\:/Users/nilsk/Zotero/storage/FAHUQPK8/367720.html:text/html}, - shorttitle = {Episodic ataxia type 1}, - urldate = {2021-06-10}, -} - -@Article{dadamo_episodic_1998, - author = {D'Adamo, Maria Cristina and Liu, Zhaoping and Adelman, John P. and Maylie, James and Pessia, Mauro}, - journal = {The EMBO Journal}, - title = {Episodic ataxia type-1 mutations in the {hKv1}.1 cytoplasmic pore region alter the gating properties of the channel}, - year = {1998}, - issn = {0261-4189}, - month = mar, - number = {5}, - pages = {1200--1207}, - volume = {17}, - abstract = {Episodic ataxia type-1 is a rare human neurological syndrome which occurs during childhood and persists through the whole life of affected patients. Several heterozygous point mutations have been found in the coding sequence of the voltage-gated potassium channel gene hKv1.1 of different affected families. V408A and E325D mutations are located in the cytoplasmic putative pore region of hKv1.1 channels and profoundly alter their gating properties. V408A channels showed increased kinetic rates of activation, deactivation and C-type inactivation. Expression of E325D channels in Xenopus oocytes led to an ?13-fold current amplitude reduction and to a 52.4 mV positive shift in the voltage dependence of activation. Moreover, the E325D mutation altered the kinetics of activation, deactivation, C-type inactivation and channel open probability. Heteromeric channels composed of two wild-type and two mutated subunits, linked as dimers, showed gating properties intermediate between channels formed from four normal or four mutated subunits. The results demonstrate that the highly conserved residues Val408 and Glu325 play a pivotal role in several gating processes of a human potassium channel, and suggest a pathogenetic mechanism by which the impairment of the delayed-rectifier function of affected neurons is related to the type and number of mutated subunits which make up the hKv1.1 channels.}, - doi = {10.1093/emboj/17.5.1200}, - file = {Full Text:C\:/Users/nilsk/Zotero/storage/65BKUWQM/D'Adamo et al. - 1998 - Episodic ataxia type-1 mutations in the hKv1.1 cyt.pdf:application/pdf;Snapshot:C\:/Users/nilsk/Zotero/storage/4ZQ529AL/17.5.html:text/html}, - keywords = {potassium channel, gating, episodic ataxia type-1, hKv1.1 channels, mutation}, - urldate = {2021-06-12}, -} - - -@Article{Leffler2005, - author = {Leffler, Andreas and Herzog, Raimund I. and Dib-Hajj, Sulayman D. and Waxman, Stephen G. and Cummins, Theodore R.}, - journal = {Pflügers Archiv}, - title = {Pharmacological properties of neuronal {TTX}-resistant sodium channels and the role of a critical serine pore residue}, - year = {2005}, - issn = {1432-2013}, - month = dec, - number = {3}, - pages = {454--463}, - volume = {451}, - abstract = {Voltage-gated sodium channels can be characterized by their sensitivity to inhibitors. Nav1.5 is sensitive to block by cadmium and extracellular QX-314, but relatively insensitive to tetrodotoxin and saxitoxin. Nav1.4 is tetrodotoxin- and saxitoxin-sensitive but resistant to cadmium and extracellular QX-314. Nav1.8 and Nav1.9 generate slowly inactivating (ITTXr-Slow) and persistent (ITTXr-Per) currents in sensory neurons that are tetrodotoxin-resistant. Tetrodotoxin sensitivity is largely determined by the identity of a single residue; tyrosine 401 in Nav1.4, cysteine 374 in Nav1.5 and serine 356 and 355 in Nav1.8 and Nav1.9. We asked whether Nav1.8 and Nav1.9 share other pharmacological properties as a result of this serine residue. ITTXr-Slow and ITTXr-Per were saxitoxin-resistant and resistant to internal QX-314. ITTXr-Slow was also resistant to external QX-314 and displayed a approximately fourfold higher sensitivity than ITTXr-Per to cadmium. The impact of the serine residue was investigated by replacing tyrosine 401 in Nav1.4 with serine (Y401S) or cysteine (Y401C). Both mutants were resistant to tetrodotoxin and saxitoxin. Whereas Nav1.4-Y401C displayed an increased sensitivity to cadmium and extracellular QX-314, the serine substitution did not alter the sensitivity of Nav1.4 to cadmium or QX-314. Our data indicates that while the serine residue determines the sensitivity of ITTXr-Slow and ITTXr-Per to tetrodotoxin and saxitoxin, it does not determine their insensitivity to QX-314 or their differential sensitivities to cadmium.}, - doi = {10.1007/s00424-005-1463-x}, - file = {:Leffler2005 - Pharmacological Properties of Neuronal TTX Resistant Sodium Channels and the Role of a Critical Serine Pore Residue.pdf:PDF}, - groups = {Jan}, - language = {english}, - urldate = {2022-04-03}, -} - -@Article{Ackerman2013, - author = {Ackerman, Michael J. and Marcou, Cherisse A. and Tester, David J.}, - journal = {Revista Española de Cardiología (English Edition)}, - title = {Personalized {Medicine}: {Genetic} {Diagnosis} for {Inherited} {Cardiomyopathies}/{Channelopathies}}, - year = {2013}, - issn = {1885-5857}, - month = apr, - number = {4}, - pages = {298--307}, - volume = {66}, - abstract = {Major advances in the field of molecular genetics have expanded our ability to identify genetic substrates underlying the pathogenesis of various disorders that follow Mendelian inheritance patterns. Included among these disorders are the potentially lethal and heritable channelopathies and cardiomyopathies for which the underlying genetic basis has been identified and is now better understood. Clinical and genetic heterogeneity are hallmark features of these disorders, with thousands of gene mutations being implicated within these divergent cardiovascular diseases. Genetic testing for several of these heritable channelopathies and cardiomyopathies has matured from discovery to research-based genetic testing to clinically/commercially available diagnostic tests. The purpose of this review is to provide the reader with a basic understanding of human medical genetics and genetic testing in the context of cardiovascular diseases of the heart. We review the state of clinical genetic testing for the more common channelopathies and cardiomyopathies, discuss some of the pertinent issues that arise from genetic testing, and discuss the future of personalized medicine in cardiovascular disease. Resumen Se han producido avances importantes en el campo de la genética molecular que han ampliado nuestra capacidad de identificar sustratos genéticos subyacentes a la patogenia de diversos trastornos que siguen patrones de herencia mendeliana. Entre estos trastornos, se encuentran las canalopatías y miocardiopatías hereditarias y potencialmente mortales con base genética subyacente identificada y que ahora se conoce mejor. La heterogeneidad clínica y genética es una característica distintiva de estos trastornos, con miles de mutaciones génicas involucradas en estas enfermedades cardiovasculares divergentes. Las pruebas genéticas en varias de estas canalopatías y miocardiopatías hereditarias han alcanzado ya la fase de madurez, tras evolucionar desde su descubrimiento a las pruebas genéticas para investigación y las pruebas diagnósticas disponibles para uso clínico/comercial. El objetivo de esta revisión es proporcionar al lector un conocimiento básico de la genética médica humana y las pruebas genéticas existentes en el contexto de las enfermedades cardiovasculares que afectan al corazón. Revisamos el estado actual de las pruebas genéticas clínicas para las canalopatías y miocardiopatías más frecuentes, tratamos asuntos pertinentes que surgen de utilizar pruebas genéticas y sobre el futuro de la medicina personalizada en las enfermedades cardiovasculares.}, - doi = {10.1016/j.rec.2012.12.010}, - groups = {Jan}, - keywords = {Genetics, Ion channels, Cardiomyopathy, Channelopathies, Genética, Canales iónicos, Miocardiopatía, Canalopatías}, - language = {english}, - shorttitle = {Personalized {Medicine}}, - urldate = {2022-03-06}, -} - -@Article{campomanes_kv_2002, - author = {Campomanes, Claire R. and Carroll, Karen I. and Manganas, Louis N. and Hershberger, Marcia E. and Gong, Belvin and Antonucci, Dana E. and Rhodes, Kenneth J. and Trimmer, James S.}, - journal = {Journal of Biological Chemistry}, - title = {Kvβ {Subunit} {Oxidoreductase} {Activity} and {Kv1} {Potassium} {Channel} {Trafficking}}, - year = {2002}, - issn = {0021-9258}, - month = mar, - number = {10}, - pages = {8298--8305}, - volume = {277}, - abstract = {Voltage-gated Kv1 potassium channels consist of pore-forming α subunits and cytoplasmic Kvβ subunits. The latter play diverse roles in modulating the gating, stability, and trafficking of Kv1 channels. The crystallographic structure of the Kvβ2 subunit revealed surprising structural homology with aldo-keto reductases, including a triosephosphate isomerase barrel structure, conservation of key catalytic residues, and a bound NADP+ cofactor (Gulbis, J. M., Mann, S., and MacKinnon, R. (1999) Cell 90, 943–952). Each Kv1-associated Kvβ subunit (Kvβ1.1, Kvβ1.2, Kvβ2, and Kvβ3) shares striking amino acid conservation in key catalytic and cofactor binding residues. Here, by a combination of structural modeling and biochemical and cell biological analyses of structure-based mutations, we investigate the potential role for putative Kvβ subunit enzymatic activity in the trafficking of Kv1 channels. We found that all Kvβ subunits promote cell surface expression of coexpressed Kv1.2 α subunits in transfected COS-1 cells. Kvβ1.1 and Kvβ2 point mutants lacking a key catalytic tyrosine residue found in the active site of all aldo-keto reductases have wild-type trafficking characteristics. However, mutations in residues within the NADP+ binding pocket eliminated effects on Kv1.2 trafficking. In cultured hippocampal neurons, Kvβ subunit coexpression led to axonal targeting of Kv1.2, recapitulating the Kv1.2 localization observed in many brain neurons. Similar to the trafficking results in COS-1 cells, mutations within the cofactor binding pocket reduced axonal targeting of Kv1.2, whereas those in the catalytic tyrosine did not. Together, these data suggest that NADP+ binding and/or the integrity of the binding pocket structure, but not catalytic activity, of Kvβ subunits is required for intracellular trafficking of Kv1 channel complexes in mammalian cells and for axonal targeting in neurons.}, - doi = {10.1074/jbc.M110276200}, - file = {ScienceDirect Full Text PDF:C\:/Users/nilsk/Zotero/storage/DQE5VCME/Campomanes et al. - 2002 - Kvβ Subunit Oxidoreductase Activity and Kv1 Potass.pdf:application/pdf;ScienceDirect Snapshot:C\:/Users/nilsk/Zotero/storage/8SLAS8NP/S0021925819364324.html:text/html}, - language = {english}, - urldate = {2021-06-12}, -} - - -@Article{Helbig2020, - author = {Helbig, Ingo and Ellis, Colin A.}, - journal = {Neuropharmacology}, - title = {Personalized medicine in genetic epilepsies – possibilities, challenges, and new frontiers}, - year = {2020}, - issn = {0028-3908}, - month = aug, - pages = {107970}, - volume = {172}, - abstract = {Identifying the optimal treatment based on specific characteristics of each patient is the main promise of precision medicine. In the field of epilepsy, the identification of more than 100 causative genes provides the enticing possibility of treatments targeted to specific disease etiologies. These conditions include classical examples, such as the use of vitamin B6 in antiquitin deficiency or the ketogenic diet in GLUT1 deficiency, where the disease mechanism can be directly addressed by the selection of a specific therapeutic compound. For epilepsies caused by channelopathies there have been advances in understanding how the selection of existing medications can be targeted to the functional consequences of genetic alterations. We discuss the examples of the use of sodium channel blockers such as phenytoin and oxcarbazepine in the sodium channelopathies, quinidine in KCNT1-related epilepsies, and strategies in GRIN-related epilepsies as examples of epilepsy precision medicine. Assessing the clinical response to targeted treatments of these conditions has been complicated by genetic and phenotypic heterogeneity, as well as by various neurological and non-neurological comorbidities. Moving forward, the development of standardized outcome measures will be critical to successful precision medicine trials in complex and heterogeneous disorders like the epilepsies. Finally, we address new frontiers in epilepsy precision medicine, including the need to match the growing volume of genetic data with high-throughput functional assays to assess the functional consequences of genetic variants and the ability to extract clinical data at large scale from electronic medical records and apply quantitative methods based on standardized phenotyping language.}, - doi = {10.1016/j.neuropharm.2020.107970}, - groups = {Jan}, - keywords = {Epilepsy, Neurogenetics, Precision medicine, Electronic medical records, Human phenotype ontology}, - language = {english}, - urldate = {2022-03-06}, -} - -@Article{marder_multiple_2011, - author = {Marder, Eve and Taylor, Adam L.}, - journal = {Nature Neuroscience}, - title = {Multiple models to capture the variability in biological neurons and networks}, - year = {2011}, - issn = {1546-1726}, - month = feb, - number = {2}, - pages = {133--138}, - volume = {14}, - abstract = {Experimental work suggests that synaptic and intrinsic neuronal properties vary considerably across identified neurons in different animals. The authors propose that instead of building a single model that captures the average behavior of a neuron or circuit, one could construct a population of models with different underlying structure and similar behaviors, as a way of investigating compensatory mechanisms that contribute to neuron and network function.}, - copyright = {2011 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.}, - doi = {10.1038/nn.2735}, - file = {Full Text PDF:C\:/Users/nilsk/Zotero/storage/P6AXF7KA/Marder and Taylor - 2011 - Multiple models to capture the variability in biol.pdf:application/pdf;Snapshot:C\:/Users/nilsk/Zotero/storage/8VI7UGLZ/nn.html:text/html}, - language = {english}, - urldate = {2021-06-17}, -} - -@Article{puopolo_roles_2007, - author = {Puopolo, Michelino and Raviola, Elio and Bean, Bruce P.}, - journal = {Journal of Neuroscience}, - title = {Roles of {Subthreshold} {Calcium} {Current} and {Sodium} {Current} in {Spontaneous} {Firing} of {Mouse} {Midbrain} {Dopamine} {Neurons}}, - year = {2007}, - month = jan, - number = {3}, - pages = {645--656}, - volume = {27}, - file = {Roles of Subthreshold Calcium Current and Sodium Current in Spontaneous Firing of Mouse Midbrain Dopamine Neurons | Journal of Neuroscience:C\:/Users/nilsk/Zotero/storage/ICI7GVB3/645.html:text/html}, -} - -@Article{ruppersberg_heteromultimeric_1990, - author = {Ruppersberg, J. Peter and Schröter, Klaus H. and Sakmann, Bert and Stocker, Martin and Sewing, Sabine and Pongs, Olaf}, - journal = {Nature}, - title = {Heteromultimeric channels formed by rat brain potassium-channel proteins}, - year = {1990}, - issn = {1476-4687}, - month = jun, - number = {6275}, - pages = {535--537}, - volume = {345}, - abstract = {AN important step towards understanding the molecular basis of the functional diversity of voltage-gated K+ channels in the mammalian brain has been the discovery of a family of genes encoding rat brain K+ channel-forming (RCK) proteins1–6. All species of these RCK proteins form homomultimeric voltage-gated K+ channels with distinct functional characteristics in Xenopus laevis oocytes following injection of the respective cRNAs2. RCK-specific mRNAs are coexpressed in several regions of the brain7, suggesting that RCK proteins also assemble into heteromultimeric K+ channels. In addition expression experiments with fractionated poly(A)+ mRNA have suggested that heteromultimeric K+ channels may occur in mammalian brain8. We report here that heteromultimeric K+ channels composed of two different RCK proteins (RCK1 and RCK4) assemble after cotransfection of HeLa cells with the corresponding cDNAs and after coinjection of the corresponding cRNAs into Xenopus oocytes. The heteromultimeric RCK1, 4 channel mediates a transient potassium outward current, similar to the RCK4 channel but inactivates more slowly, has a larger conductance and is more sensitive to block by dendrotoxin and tetraethylammonium chloride.}, - copyright = {1990 Nature Publishing Group}, - doi = {10.1038/345535a0}, - file = {Full Text PDF:C\:/Users/nilsk/Zotero/storage/9MTQJWHB/Ruppersberg et al. - 1990 - Heteromultimeric channels formed by rat brain pota.pdf:application/pdf;Snapshot:C\:/Users/nilsk/Zotero/storage/8TLMQMQM/345535a0.html:text/html}, - language = {english}, - urldate = {2021-06-12}, -} - -@Article{barreiro_-current_2012, - author = {Barreiro, Andrea K. and Thilo, Evan L. and Shea-Brown, Eric}, - journal = {Journal of Neurophysiology}, - title = {A-current and type {I}/type {II} transition determine collective spiking from common input}, - year = {2012}, - issn = {0022-3077}, - month = sep, - number = {6}, - pages = {1631--1645}, - volume = {108}, - abstract = {The mechanisms and impact of correlated, or synchronous, firing among pairs and groups of neurons are under intense investigation throughout the nervous system. A ubiquitous circuit feature that can give rise to such correlations consists of overlapping, or common, inputs to pairs and populations of cells, leading to common spike train responses. Here, we use computational tools to study how the transfer of common input currents into common spike outputs is modulated by the physiology of the recipient cells. We focus on a key conductance, gA, for the A-type potassium current, which drives neurons between “type II” excitability (low gA), and “type I” excitability (high gA). Regardless of gA, cells transform common input fluctuations into a tendency to spike nearly simultaneously. However, this process is more pronounced at low gA values. Thus, for a given level of common input, type II neurons produce spikes that are relatively more correlated over short time scales. Over long time scales, the trend reverses, with type II neurons producing relatively less correlated spike trains. This is because these cells' increased tendency for simultaneous spiking is balanced by an anticorrelation of spikes at larger time lags. These findings extend and interpret prior findings for phase oscillators to conductance-based neuron models that cover both oscillatory (superthreshold) and subthreshold firing regimes. We demonstrate a novel implication for neural signal processing: downstream cells with long time constants are selectively driven by type I cell populations upstream and those with short time constants by type II cell populations. Our results are established via high-throughput numerical simulations and explained via the cells' filtering properties and nonlinear dynamics.}, - doi = {10.1152/jn.00928.2011}, - file = {Full Text PDF:C\:/Users/nilsk/Zotero/storage/4CWLP49S/Barreiro et al. - 2012 - A-current and type Itype II transition determine .pdf:application/pdf;Snapshot:C\:/Users/nilsk/Zotero/storage/B37GK9MB/jn.00928.html:text/html;Submitted Version:C\:/Users/nilsk/Zotero/storage/GRCRXMAN/Barreiro et al. - 2012 - A-current and type Itype II transition determine .pdf:application/pdf}, - urldate = {2020-10-27}, -} - -@Article{lauxmann_therapeutic_2021, - author = {Lauxmann, Stephan and Sonnenberg, Lukas and Koch, Nils A. and Boßelmann, Christian Malte and Winter, Natalie and Schwarz, Niklas and Wuttke, Thomas Volkmar and Hedrich, Ulrike B. S. and Liu, Yuanyuan and Lerche, Holger and Benda, Jan and Kegele, Josua}, - journal = {Frontiers in Neurology}, - title = {Therapeutic potential of sodium channel blockers as targeted therapy approach in {KCNA1}-associated episodic ataxia ({EA1}) and a comprehensive review of the literature}, - year = {2021}, - issn = {1664-2295}, - volume = {In Press}, - abstract = {Among genetic paroxysmal movement disorders, variants in ion channel coding genes constitute a major subgroup. Loss-of-function (LOF) variants in KCNA1, the coding gene for KV1.1 channels, are associated with episodic ataxia type 1 (EA1), characterized by seconds to minutes-lasting attacks including gait incoordination, limb ataxia, truncal instability, dysarthria, nystagmus, tremor, occasionally seizures, but also persistent neuromuscular symptoms like myokymia or neuromyotonia. Standard treatment has not been developed yet and different treatment efforts need to be systematically evaluated. Personalized therapeutic regimens tailored to disease-causing pathophysiological mechanisms may offer the specificity required to overcome limitations in therapy. Toward this aim, we (i) reviewed all available clinical reports on treatment response and functional consequences of KCNA1 variants causing EA1, (ii) examined the potential effects on neuronal excitability of all variants using a predictive scoring system for ion channel variants based on single compartment conductance-based models, (iii) set out to assess a variety of SCBs (Phenytoin, lamotrigine, carbamazepine, and riluzole) regarding their potential to restore the identified underlying pathophysiological mechanisms of KV1.1 channels and (iv) provide a comprehensive review of the literature considering all types of episodic ataxia. Reviewing the treatment efforts of EA1 patients revealed moderate response to acetazolamide and exhibited the strength of sodium channel blockers (SCBs) in the treatment of EA1 patients. Biophysical dysfunction of Kv1.1 channels is typically based on depolarizing shifts of steady-state activation, leading to a loss-of-function of KCNA1 variant channels. Our model predicts a broadening of the action potentials, a lowered rheobase to more hyperpolarized potentials and an increase of the firing rate. Predicted effects of phenytoin, carbamazepine and riluzole could partially restore the altered gating properties of dysfunctional variant channels. These data strengthen the great potential of SCBs by contributing to functional compensation of dysfunctional Kv1.1 channels, propose riluzole as a new drug repurposing candidate and highlight the role of personalized approaches to develop standard care for EA1 patients. These results could have implications for clinical practice in future and highlight the need for the development of individualized and targeted therapies for episodic ataxia and genetic paroxysmal disorders in general.}, - doi = {10.3389/fneur.2021.703970}, - keywords = {conduction-based model, episodic ataxia, Kcna1, KV1.1, Paroxysmal movement disorders, precision medicine, Riluzole, Sodium Channel Blockers, Voltage-gated potassium channels}, - language = {English}, - urldate = {2021-07-28}, -} - - -@Article{Kispersky2012, - author = {Kispersky, Tilman J. and Caplan, Jonathan S. and Marder, Eve}, - journal = {Journal of Neuroscience}, - title = {Increase in {Sodium} {Conductance} {Decreases} {Firing} {Rate} and {Gain} in {Model} {Neurons}}, - year = {2012}, - issn = {0270-6474, 1529-2401}, - month = aug, - number = {32}, - pages = {10995--11004}, - volume = {32}, - abstract = {We studied the effects of increased sodium conductance on firing rate and gain in two populations of conductance-based, single-compartment model neurons. The first population consisted of 1000 model neurons with differing values of seven voltage-dependent conductances. In many of these models, increasing the sodium conductance threefold unexpectedly reduced the firing rate and divisively scaled the gain at high input current. In the second population, consisting of 1000 simplified model neurons, we found that enhanced sodium conductance changed the frequency–current (FI) curve in two computationally distinct ways, depending on the firing rate. In these models, increased sodium conductance produced a subtractive shift in the FI curve at low firing rates because the additional sodium conductance allowed the neuron to respond more strongly to equivalent input current. In contrast, at high input current, the increase in sodium conductance resulted in a divisive change in the gain because the increased conductance produced a proportionally larger activation of the delayed rectifier potassium conductance. The control and sodium-enhanced FI curves intersect at a point that delimits two regions in which the same biophysical manipulation produces two fundamentally different changes to the model neuron's computational properties. This suggests a potentially difficult problem for homeostatic regulation of intrinsic excitability.}, - chapter = {Articles}, - copyright = {Copyright © 2012 the authors 0270-6474/12/3210995-10\$15.00/0}, - doi = {10.1523/JNEUROSCI.2045-12.2012}, - groups = {Jan}, - language = {english}, - pmid = {22875933}, - publisher = {Society for Neuroscience}, - urldate = {2022-03-05}, -} - -@Article{alexander_cerebellar_2019, - author = {Alexander, Ryan P. D. and Mitry, John and Sareen, Vasu and Khadra, Anmar and Bowie, Derek}, - journal = {eNeuro}, - title = {Cerebellar {Stellate} {Cell} {Excitability} {Is} {Coordinated} by {Shifts} in the {Gating} {Behavior} of {Voltage}-{Gated} {Na}+ and {A}-{Type} {K}+ {Channels}}, - year = {2019}, - issn = {2373-2822}, - month = may, - number = {3}, - volume = {6}, - abstract = {Neuronal excitability in the vertebrate brain is governed by the coordinated activity of both ligand- and voltage-gated ion channels. In the cerebellum, spontaneous action potential (AP) firing of inhibitory stellate cells (SCs) is variable, typically operating within the 5- to 30-Hz frequency range. AP frequency is shaped by the activity of somatodendritic A-type K+ channels and the inhibitory effect of GABAergic transmission. An added complication, however, is that whole-cell recording from SCs induces a time-dependent and sustained increase in membrane excitability making it difficult to define the full range of firing rates. Here, we show that whole-cell recording in cerebellar SCs of both male and female mice augments firing rates by reducing the membrane potential at which APs are initiated. AP threshold is lowered due to a hyperpolarizing shift in the gating behavior of voltage-gated Na+ channels. Whole-cell recording also elicits a hyperpolarizing shift in the gating behavior of A-type K+ channels which contributes to increased firing rates. Hodgkin–Huxley modeling and pharmacological experiments reveal that gating shifts in A-type K+ channel activity do not impact AP threshold, but rather promote channel inactivation which removes restraint on the upper limit of firing rates. Taken together, our work reveals an unappreciated impact of voltage-gated Na+ channels that work in coordination with A-type K+ channels to regulate the firing frequency of cerebellar SCs.}, - copyright = {Copyright © 2019 Alexander et al.. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.}, - doi = {10.1523/ENEURO.0126-19.2019}, - file = {Full Text PDF:C\:/Users/nilsk/Zotero/storage/FJT2PTDH/alexander_cerebellar_2019 - Cerebellar Stellate Cell Excitability Is Coordinated by Shifts in the Gating Behavior of Voltage Gated Na+ and a Type K+ Channels.pdf:application/pdf;Snapshot:C\:/Users/nilsk/Zotero/storage/GQVXJ8F2/ENEURO.0126-19.html:text/html}, - keywords = {cerebellum, action potential, A-type potassium channel, computational modeling, sodium channel, stellate cell}, - language = {english}, - urldate = {2021-04-13}, -} - -@Article{jonas_regulation_1996, - author = {Jonas, Elizabeth A and Kaczmarek, Leonard K}, - journal = {Current Opinion in Neurobiology}, - title = {Regulation of potassium channels by protein kinases}, - year = {1996}, - issn = {0959-4388}, - month = jun, - number = {3}, - pages = {318--323}, - volume = {6}, - abstract = {Studies of the role of protein phosphorylation in the modulation of neuronal excitability are beginning to identify specific sites on ion channels that are substrates for serine/threonine kinases and that contribute to short-term and long-term regulation of current amplitude and kinetics. In addition, it is becoming apparent that phosphorylation of tyrosine residues may produce acute changes in the characteristics of ion channels. These recent findings are best illustrated by examining the Shaker superfamily of potassium channels.}, - doi = {10.1016/S0959-4388(96)80114-0}, - file = {ScienceDirect Full Text PDF:C\:/Users/nilsk/Zotero/storage/3GZJ4IP9/Jonas and Kaczmarek - 1996 - Regulation of potassium channels by protein kinase.pdf:application/pdf;ScienceDirect Snapshot:C\:/Users/nilsk/Zotero/storage/M3UBSIZQ/S0959438896801140.html:text/html}, - language = {english}, - urldate = {2021-06-12}, -} - -@Article{hafez_altered_2020, - author = {Hafez, Omar A. and Gottschalk, Allan}, - journal = {Journal of Computational Neuroscience}, - title = {Altered neuronal excitability in a {Hodgkin}-{Huxley} model incorporating channelopathies of the delayed rectifier potassium channel}, - year = {2020}, - issn = {1573-6873}, - month = nov, - number = {4}, - pages = {377--386}, - volume = {48}, - abstract = {Channelopathies involving acquired or genetic modifications of the delayed rectifier K+ channel Kv1.1 include phenotypes characterized by enhanced neuronal excitability. Affected Kv1.1 channels exhibit combinations of altered expression, voltage sensitivity, and rates of activation and deactivation. Computational modeling and analysis can reveal the potential of particular channelopathies to alter neuronal excitability. A dynamical systems approach was taken to study the excitability and underlying dynamical structure of the Hodgkin-Huxley (HH) model of neural excitation as properties of the delayed rectifier K+ channel were altered. Bifurcation patterns of the HH model were determined as the amplitude of steady injection current was varied simultaneously with single parameters describing the delayed rectifier rates of activation and deactivation, maximal conductance, and voltage sensitivity. Relatively modest changes in the properties of the delayed rectifier K+ channel analogous to what is described for its channelopathies alter the bifurcation structure of the HH model and profoundly modify excitability of the HH model. Channelopathies associated with Kv1.1 can reduce the threshold for onset of neural activity. These studies also demonstrate how pathological delayed rectifier K+ channels could lead to the observation of the generalized Hopf bifurcation and, perhaps, other variants of the Hopf bifurcation. The observed bifurcation patterns collectively demonstrate that properties of the nominal delayed rectifier in the HH model appear optimized to permit activation of the HH model over the broadest possible range of input currents.}, - doi = {10.1007/s10827-020-00766-1}, - file = {Springer Full Text PDF:C\:/Users/nilsk/Zotero/storage/4CCGDHXQ/Hafez and Gottschalk - 2020 - Altered neuronal excitability in a Hodgkin-Huxley .pdf:application/pdf}, - language = {english}, - urldate = {2021-07-26}, -} - -@Article{rettig_inactivation_1994, - author = {Rettig, Jens and Heinemann, Stefan H. and Wunder, Frank and Lorra, Christoph and Parcej, David N. and Oliver Dolly, J. and Pongs, Olaf}, - journal = {Nature}, - title = {Inactivation properties of voltage-gated {K} + channels altered by presence of β-subunit}, - year = {1994}, - issn = {1476-4687}, - month = may, - number = {6478}, - pages = {289--294}, - volume = {369}, - abstract = {Structural and functional diversity of voltage-gated Kv1-type potassium channels in rat brain is enhanced by the association of two different types of subunits, the membrane-bound, pore-forming α-subunits and a peripheral β-subunit. We have cloned a β-subunit (Kvβ1) that is specifically expressed in the rat nervous system. Association of Kvβ1 with α-subunits confers rapid A-type inactivation on non-inactivating Kv1 channels (delayed rectifiers) in expression systems in vitro. This effect is mediated by an inactivating ball domain in the Kvβ1 amino terminus.}, - copyright = {1994 Nature Publishing Group}, - doi = {10.1038/369289a0}, - file = {Full Text PDF:C\:/Users/nilsk/Zotero/storage/RCEYBSD2/Rettig et al. - 1994 - Inactivation properties of voltage-gated K + chann.pdf:application/pdf;Full Text PDF:C\:/Users/nilsk/Zotero/storage/9X7D2PY4/Rettig et al. - 1994 - Inactivation properties of voltage-gated K + chann.pdf:application/pdf;Snapshot:C\:/Users/nilsk/Zotero/storage/WYSLLXAL/369289a0.html:text/html;Snapshot:C\:/Users/nilsk/Zotero/storage/WCK725TD/369289a0.html:text/html}, - language = {english}, - urldate = {2021-06-07}, -} - -@Article{saltelli_how_2010, - author = {Saltelli, Andrea and Annoni, Paola}, - journal = {Environmental Modelling \& Software}, - title = {How to avoid a perfunctory sensitivity analysis}, - year = {2010}, - issn = {1364-8152}, - month = dec, - number = {12}, - pages = {1508--1517}, - volume = {25}, - abstract = {Mathematical modelers from different disciplines and regulatory agencies worldwide agree on the importance of a careful sensitivity analysis (SA) of model-based inference. The most popular SA practice seen in the literature is that of ’one-factor-at-a-time’ (OAT). This consists of analyzing the effect of varying one model input factor at a time while keeping all other fixed. While the shortcomings of OAT are known from the statistical literature, its widespread use among modelers raises concern on the quality of the associated sensitivity analyses. The present paper introduces a novel geometric proof of the inefficiency of OAT, with the purpose of providing the modeling community with a convincing and possibly definitive argument against OAT. Alternatives to OAT are indicated which are based on statistical theory, drawing from experimental design, regression analysis and sensitivity analysis proper.}, - doi = {10.1016/j.envsoft.2010.04.012}, - file = {ScienceDirect Full Text PDF:C\:/Users/nilsk/Zotero/storage/SWBUI32R/Saltelli and Annoni - 2010 - How to avoid a perfunctory sensitivity analysis.pdf:application/pdf;ScienceDirect Full Text PDF:C\:/Users/nilsk/Zotero/storage/P9EGLCTE/Saltelli and Annoni - 2010 - How to avoid a perfunctory sensitivity analysis.pdf:application/pdf;ScienceDirect Snapshot:C\:/Users/nilsk/Zotero/storage/JLYYH3WR/S1364815210001180.html:text/html}, - keywords = {Mathematical modeling, One-at-a-time, Robustness, Sensitivity analysis, Uncertainty analysis}, - language = {english}, - urldate = {2021-06-02}, -} - - -@Article{Hedrich14874, - author = {Hedrich, Ulrike B.S. and Liautard, Camille and Kirschenbaum, Daniel and Pofahl, Martin and Lavigne, Jennifer and Liu, Yuanyuan and Theiss, Stephan and Slotta, Johannes and Escayg, Andrew and Dihn{\'e}, Marcel and Beck, Heinz and Mantegazza, Massimo and Lerche, Holger}, - journal = {Journal of Neuroscience}, - title = {Impaired Action Potential Initiation in GABAergic Interneurons Causes Hyperexcitable Networks in an Epileptic Mouse Model Carrying a Human NaV1.1 Mutation}, - year = {2014}, - issn = {0270-6474}, - number = {45}, - pages = {14874--14889}, - volume = {34}, - abstract = {Mutations in SCN1A and other ion channel genes can cause different epileptic phenotypes, but the precise mechanisms underlying the development of hyperexcitable networks are largely unknown. Here, we present a multisystem analysis of an SCN1A mouse model carrying the NaV1.1-R1648H mutation, which causes febrile seizures and epilepsy in humans. We found a ubiquitous hypoexcitability of interneurons in thalamus, cortex, and hippocampus, without detectable changes in excitatory neurons. Interestingly, somatic Na+ channels in interneurons and persistent Na+ currents were not significantly changed. Instead, the key mechanism of interneuron dysfunction was a deficit of action potential initiation at the axon initial segment that was identified by analyzing action potential firing. This deficit increased with the duration of firing periods, suggesting that increased slow inactivation, as recorded for recombinant mutated channels, could play an important role. The deficit in interneuron firing caused reduced action potential-driven inhibition of excitatory neurons as revealed by less frequent spontaneous but not miniature IPSCs. Multiple approaches indicated increased spontaneous thalamocortical and hippocampal network activity in mutant mice, as follows: (1) more synchronous and higher-frequency firing was recorded in primary neuronal cultures plated on multielectrode arrays; (2) thalamocortical slices examined by field potential recordings revealed spontaneous activities and pathological high-frequency oscillations; and (3) multineuron Ca2+ imaging in hippocampal slices showed increased spontaneous neuronal activity. Thus, an interneuron-specific generalized defect in action potential initiation causes multisystem disinhibition and network hyperexcitability, which can well explain the occurrence of seizures in the studied mouse model and in patients carrying this mutation.}, - doi = {10.1523/JNEUROSCI.0721-14.2014}, - eprint = {https://www.jneurosci.org/content/34/45/14874.full.pdf}, - publisher = {Society for Neuroscience}, -} - - - - -@Article{makinson_scn1a_2016, - author = {Makinson, Christopher D. and Dutt, Karoni and Lin, Frank and Papale, Ligia A. and Shankar, Anupama and Barela, Arthur J. and Liu, Robert and Goldin, Alan L. and Escayg, Andrew}, - journal = {Experimental Neurology}, - title = {An {Scn1a} epilepsy mutation in {Scn8a} alters seizure susceptibility and behavior}, - year = {2016}, - issn = {0014-4886}, - pages = {46--58}, - volume = {275}, - abstract = {Understanding the role of SCN8A in epilepsy and behavior is critical in light of recently identified human SCN8A epilepsy mutations. We have previously demonstrated that Scn8amed and Scn8amed-jo mice carrying mutations in the Scn8a gene display increased resistance to flurothyl and kainic acid-induced seizures; however, they also exhibit spontaneous absence seizures. To further investigate the relationship between altered SCN8A function and epilepsy, we introduced the SCN1A-R1648H mutation, identified in a family with generalized epilepsy with febrile seizures plus (GEFS+), into the corresponding position (R1627H) of the mouse Scn8a gene. Heterozygous R1627H mice exhibited increased resistance to some forms of pharmacologically and electrically induced seizures and the mutant Scn8a allele ameliorated the phenotype of Scn1a-R1648H mutants. Hippocampal slices from heterozygous R1627H mice displayed decreased bursting behavior compared to wild-type littermates. Paradoxically, at the homozygous level, R1627H mice did not display increased seizure resistance and were susceptible to audiogenic seizures. We furthermore observed increased hippocampal pyramidal cell excitability in heterozygous and homozygous Scn8a-R1627H mutants, and decreased interneuron excitability in heterozygous Scn8a-R1627H mutants. These results expand the phenotypes associated with disruption of the Scn8a gene and demonstrate that an Scn8a mutation can both confer seizure protection and increase seizure susceptibility.}, - doi = {10.1016/j.expneurol.2015.09.008}, - keywords = {Audiogenic seizure, Dravet syndrome, GEFS+, Interneuron, Na1.1, Na1.6, Sodium channel, Voltage sensor}, -} - -@Article{parker_periodic_1946, - author = {Parker, H. L.}, - title = {Periodic ataxia}, - issn = {0095-9677}, - language = {english}, - pages = {642--645}, - volume = {38}, - journal = {Collected Papers of the Mayo Clinic and the Mayo Foundation. Mayo Clinic}, - keywords = {Humans, Ataxia, ATAXIA, Spinocerebellar Degenerations}, - year = {1946}, -} - - - -@Article{Waxman2007, - author = {Waxman, Stephen G.}, - journal = {Nature Neuroscience}, - title = {Channel, neuronal and clinical function in sodium channelopathies: from genotype to phenotype}, - year = {2007}, - issn = {1546-1726}, - month = apr, - number = {4}, - pages = {405--409}, - volume = {10}, - abstract = {What is the relationship between sodium channel function, neuronal function and clinical status in channelopathies of the nervous system? Given the central role of sodium channels in the generation of neuronal activity, channelopathies involving sodium channels might be expected to cause either enhanced sodium channel function and neuronal hyperexcitability associated with positive clinical manifestations such as seizures, or attenuated channel function and neuronal hypoexcitability associated with negative clinical manifestations such as paralysis. In this article, I review observations showing that changes in neuronal function and clinical status associated with channelopathies are not necessarily predictable solely from the altered physiological properties of the mutated channel itself. I discuss evidence showing that cell background acts as a filter that can strongly influence the effects of ion channel mutations.}, - copyright = {2007 Nature Publishing Group}, - doi = {10.1038/nn1857}, - groups = {Jan}, - keywords = {Biomedicine, general, Neurosciences, Behavioral Sciences, Biological Techniques, Neurobiology, Animal Genetics and Genomics}, - language = {english}, - publisher = {Nature Publishing Group}, - shorttitle = {Channel, neuronal and clinical function in sodium channelopathies}, - urldate = {2022-03-03}, -} - - -@Article{Brunklaus2022, - author = {Brunklaus, Andreas and Feng, Tony and Brünger, Tobias and Perez-Palma, Eduardo and Heyne, Henrike and Matthews, Emma and Semsarian, Christopher and Symonds, Joseph D. and Zuberi, Sameer M. and Lal, Dennis and Schorge, Stephanie}, - journal = {Brain}, - title = {Gene variant effects across sodium channelopathies predict function and guide precision therapy}, - year = {2022}, - issn = {0006-8950}, - month = jan, - pages = {awac006}, - abstract = {Pathogenic variants in the voltage-gated sodium channel gene family (SCNs) lead to early onset epilepsies, neurodevelopmental disorders, skeletal muscle channelopathies, peripheral neuropathies and cardiac arrhythmias. Disease-associated variants have diverse functional effects ranging from complete loss-of-function to marked gain-of-function. Therapeutic strategy is likely to depend on functional effect. Experimental studies offer important insights into channel function, but are resource intensive and only performed in a minority of cases. Given the evolutionarily conserved nature of the sodium channel genes we investigated whether similarities in biophysical properties between different voltage-gated sodium channels can predict function and inform precision treatment across sodium channelopathies. We performed a systematic literature search identifying functionally assessed variants in any of the nine voltage-gated sodium channel genes until 28 April 2021. We included missense variants that had been electrophysiologically characterised in mammalian cells in whole-cell patch-clamp recordings. We performed an alignment of linear protein sequences of all sodium channel genes and correlated variants by their overall functional effect on biophysical properties. Of 951 identified records, 437 sodium channel-variants met our inclusion criteria and were reviewed for functional properties. Of these, 141 variants were epilepsy-associated (SCN1/2/3/8A), 79 had a neuromuscular phenotype (SCN4/9/10/11A), 149 were associated with a cardiac phenotype (SCN5/10A) and 68 (16\%) were considered benign. We detected 38 missense variant pairs with an identical disease-associated variant in a different sodium channel gene. 35 out of 38 of those pairs resulted in similar functional consequences indicating up to 92\% biophysical agreement between corresponding sodium channel variants (odds ratio = 11.3; 95\% CI = 2.8 to 66.9; P \< 0.001). Pathogenic missense variants were clustered in specific functional domains, whereas population variants were significantly more frequent across non conserved domains (odds ratio = 18.6; 95\% CI = 10.9 to 34.4; P \< 0.001). Pore-loop regions were frequently associated with loss-of-function (LoF) variants, whereas inactivation sites were associated with gain-of-function (GoF; odds ratio = 42.1, 95\% CI = 14.5 to 122.4; P \< 0.001), whilst variants occurring in voltage-sensing regions comprised a range of gain- and loss-of-function effects. Our findings suggest that biophysical characterisation of variants in one SCN-gene can predict channel function across different SCN-genes where experimental data are not available. The collected data represent the first GoF versus LoF topological map of SCN proteins indicating shared patterns of biophysical effects aiding variant analysis and guiding precision therapy. We integrated our findings into a free online webtool to facilitate functional sodium channel gene variant interpretation (http://SCN-viewer.broadinstitute.org).}, - doi = {10.1093/brain/awac006}, - file = {:Brunklaus2022 - Gene Variant Effects across Sodium Channelopathies Predict Function and Guide Precision Therapy.pdf:PDF}, - groups = {Jan}, - urldate = {2022-03-06}, -} - -@Article{goaillard_ion_2021, - author = {Goaillard, Jean-Marc and Marder, Eve}, - journal = {Annual Review of Neuroscience}, - title = {Ion {Channel} {Degeneracy}, {Variability}, and {Covariation} in {Neuron} and {Circuit} {Resilience}}, - year = {2021}, - issn = {0147-006X}, - month = jul, - abstract = {The large number of ion channels found in all nervous systems poses fundamental questions concerning how the characteristic intrinsic properties of single neurons are determined by the specific subsets of channels they express. All neurons display many different ion channels with overlapping voltage- and time-dependent properties. We speculate that these overlapping properties promote resilience in neuronal function. Individual neurons of the same cell type show variability in ion channel conductance densities even though they can generate reliable and similar behavior. This complicates a simple assignment of function to any conductance and is associated with variable responses of neurons of the same cell type to perturbations, deletions, and pharmacological manipulation. Ion channel genes often show strong positively correlated expression, which may result from the molecular and developmental rules that determine which ion channels are expressed in a given cell type. Expected final online publication date for the Annual Review of Neuroscience, Volume 44 is July 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.}, - doi = {10.1146/annurev-neuro-092920-121538}, - file = {Full Text PDF:C\:/Users/nilsk/Zotero/storage/CLGI3EBW/Goaillard and Marder - 2021 - Ion Channel Degeneracy, Variability, and Covariati.pdf:application/pdf;Snapshot:C\:/Users/nilsk/Zotero/storage/MVGHAFMQ/annurev-neuro-092920-121538.html:text/html}, - urldate = {2021-07-01}, -} - -@Article{Weber2017, - author = {Weber, Yvonne G. and Biskup, Saskia and Helbig, Katherine L. and Von Spiczak, Sarah and Lerche, Holger}, - journal = {Expert Review of Molecular Diagnostics}, - title = {The role of genetic testing in epilepsy diagnosis and management}, - year = {2017}, - issn = {1473-7159}, - month = aug, - number = {8}, - pages = {739--750}, - volume = {17}, - abstract = {Introduction: Epilepsy is a common neurological disorder characterized by recurrent unprovoked seizures. More than 500 epilepsy-associated genes have been described in the literature. Most of these genes play an important role in neuronal excitability, cortical development or synaptic transmission. A growing number of genetic variations have implications on diagnosis and prognostic or therapeutic advice in terms of a personalized medicine.Area covered: The review presents the different forms of genetic epilepsies with respect to their underlying genetic and functional pathophysiology and aims to give advice for recommended genetic testing. Moreover, it discusses ethical and legal guidelines, costs and technical limitations which should be considered.Expert commentary: Genetic testing is an important component in the diagnosis and treatment of many forms of epilepsy.}, - doi = {10.1080/14737159.2017.1335598}, - groups = {Jan}, - keywords = {Genetic counseling, next generation sequencing, microarray analysis, exome, genome, idiopathic, personalized medicine, precision medicine, metabolic epilepsies, genetic epilepsies}, - pmid = {28548558}, - publisher = {Taylor \& Francis}, - urldate = {2022-03-06}, -} - -@Article{glasscock_kv11_2019, - author = {Glasscock, Edward}, - journal = {Channels}, - title = {Kv1.1 channel subunits in the control of neurocardiac function}, - year = {2019}, - issn = {1933-6950}, - month = jan, - number = {1}, - pages = {299--307}, - volume = {13}, - abstract = {Voltage-gated Kv1.1 potassium channel α-subunits are broadly expressed in the nervous system where they act as critical regulators of neuronal excitability. Mutations in the KCNA1 gene, which encodes Kv1.1, are associated with the neurological diseases episodic ataxia and epilepsy. Studies in mouse models have shown that Kv1.1 is important for neural control of the heart and that Kcna1 deletion leads to cardiac dysfunction that appears to be brain-driven. Traditionally, KCNA1 was not believed to be expressed in the heart. However, recent studies have revealed that Kv1.1 subunits are not only present in cardiomyocytes, but that they also make an important heart-intrinsic functional contribution to outward K+ currents and action potential repolarization. This review recounts the winding history of discovery of KCNA1 gene expression and neurocardiac function from fruit flies to mammals and from brain to heart and looks at some of the salient questions that remain to be answered regarding emerging cardiac roles of Kv1.1.}, - doi = {10.1080/19336950.2019.1635864}, - file = {Full Text PDF:C\:/Users/nilsk/Zotero/storage/9HL7ES5Y/Glasscock - 2019 - Kv1.1 channel subunits in the control of neurocard.pdf:application/pdf;Snapshot:C\:/Users/nilsk/Zotero/storage/QZIHSRYT/19336950.2019.html:text/html}, - keywords = {epilepsy, action potential, Kv1.1, SUDEP, heart, Kcna1}, - urldate = {2021-06-10}, -} - -@Article{brunt_familial_1990, - author = {Brunt, Ewout R. P. and van Weerden, Tiemen W.}, - journal = {Brain}, - title = {Familial {Paroxysmal} {Kinesigenic} {Ataxia} and {Continuous} {Myokymia}}, - year = {1990}, - issn = {0006-8950}, - month = oct, - number = {5}, - pages = {1361--1382}, - volume = {113}, - abstract = {A large family with paroxysmal ataxia and continuous myokymic discharges is described. The disorder is of autosomal dominant inheritance. During attacks coordination of movements and balance are disturbed; often a postural tremor of the head and the hands and fine twitching in some of the facial and hand muscles are present. The attacks usually last a few minutes and may occur several times per day. They first appear in childhood and tend to abate after early adulthood. The attacks are frequently precipitated by kinesigenic stimuli similar to those in paroxysmal kinesigenic choreoathetosis. Their occurrence can be reduced or prevented by carbonic anhydrase inhibitors. Between attacks a slight postural tremor and ataxia was found in a few of the elderly affected members. Fine rippling myokymia was obvious in a few and could be detected on close inspection in about half of the adults. Electromyography (EMG) showed myokymic discharges in all affected members. The characteristics and reactivity of this myokymic activity suggest multiple impulse generation in the peripheral nerves.}, - doi = {10.1093/brain/113.5.1361}, - file = {Full Text PDF:C\:/Users/nilsk/Zotero/storage/558YAH37/BRUNT and VAN WEERDEN - 1990 - FAMILIAL PAROXYSMAL KINESIGENIC ATAXIA AND CONTINU.pdf:application/pdf;Snapshot:C\:/Users/nilsk/Zotero/storage/2PIA368R/267626.html:text/html}, - urldate = {2021-06-10}, -} - -@Article{taylor_how_2009, - author = {Taylor, Adam L. and Goaillard, Jean-Marc and Marder, Eve}, - journal = {Journal of Neuroscience}, - title = {How {Multiple} {Conductances} {Determine} {Electrophysiological} {Properties} in a {Multicompartment} {Model}}, - year = {2009}, - month = apr, - number = {17}, - pages = {5573--5586}, - volume = {29}, - file = {How Multiple Conductances Determine Electrophysiological Properties in a Multicompartment Model | Journal of Neuroscience:C\:/Users/nilsk/Zotero/storage/46GADMUG/5573.html:text/html}, -} - -@Article{ranjan_kinetic_2019, - author = {Ranjan, Rajnish and Logette, Emmanuelle and Marani, Michela and Herzog, Mirjia and Tâche, Valérie and Scantamburlo, Enrico and Buchillier, Valérie and Markram, Henry}, - journal = {Frontiers in Cellular Neuroscience}, - title = {A {Kinetic} {Map} of the {Homomeric} {Voltage}-{Gated} {Potassium} {Channel} ({Kv}) {Family}}, - year = {2019}, - issn = {1662-5102}, - volume = {13}, - abstract = {The voltage-gated potassium (Kv) channels, encoded by 40 genes, repolarize all electrically excitable cells, including plant, cardiac and neuronal cells. Although these genes were fully sequenced decades ago, a comprehensive kinetic characterization of all Kv channels is still missing, especially near physiological temperature. Here, we present a standardized kinetic map of the 40 homomeric Kv channels systematically characterized at 15°C, 25°C and 35°C. Importantly, the Kv kinetics at 35°C differ significantly from commonly reported kinetics, usually performed at room temperature. We observed voltage-dependent Q10 for all active Kv channels and inherent heterogeneity in kinetics for some of them. Kinetic properties are consistent across different host cell lines and conserved across mouse, rat and human. All electrophysiology data from all Kv channels are made available through public website (Channelpedia). This dataset provides a solid foundation for exploring kinetics of heteromeric channels, roles of auxiliary subunits, kinetic modulation, and for building accurate Kv models.}, - doi = {10.3389/fncel.2019.00358}, - file = {Full Text PDF:C\:/Users/nilsk/Zotero/storage/JP3ET4D5/Ranjan et al. - 2019 - A Kinetic Map of the Homomeric Voltage-Gated Potas.pdf:application/pdf}, - keywords = {Kinetics, automated patch clamp electrophysiology, CHO - Chinese hamster ovary, ion channel, Kv}, - language = {English}, - urldate = {2021-02-16}, -} - -@Article{pospischil_minimal_2008, - author = {Pospischil, Martin and Toledo-Rodriguez, Maria and Monier, Cyril and Piwkowska, Zuzanna and Bal, Thierry and Frégnac, Yves and Markram, Henry and Destexhe, Alain}, - journal = {Biological Cybernetics}, - title = {Minimal {Hodgkin}–{Huxley} type models for different classes of cortical and thalamic neurons}, - year = {2008}, - issn = {1432-0770}, - month = nov, - number = {4}, - pages = {427--441}, - volume = {99}, - abstract = {We review here the development of Hodgkin–Huxley (HH) type models of cerebral cortex and thalamic neurons for network simulations. The intrinsic electrophysiological properties of cortical neurons were analyzed from several preparations, and we selected the four most prominent electrophysiological classes of neurons. These four classes are “fast spiking” “regular spiking” “intrinsically bursting” and “low-threshold spike” cells. For each class, we fit “minimal” HH type models to experimental data. The models contain the minimal set of voltage-dependent currents to account for the data. To obtain models as generic as possible, we used data from different preparations in vivo and in vitro, such as rat somatosensory cortex and thalamus, guinea-pig visual and frontal cortex, ferret visual cortex, cat visual cortex and cat association cortex. For two cell classes, we used automatic fitting procedures applied to several cells, which revealed substantial cell-to-cell variability within each class. The selection of such cellular models constitutes a necessary step towards building network simulations of the thalamocortical system with realistic cellular dynamical properties.}, - doi = {10.1007/s00422-008-0263-8}, - file = {Springer Full Text PDF:C\:/Users/nilsk/Zotero/storage/SGVJJSXF/Pospischil et al. - 2008 - Minimal Hodgkin–Huxley type models for different c.pdf:application/pdf}, - language = {english}, - urldate = {2020-09-23}, -} - -@Article{wang_localization_1994, - author = {Wang, H. and Kunkel, D. D. and Schwartzkroin, P. A. and Tempel, B. L.}, - journal = {Journal of Neuroscience}, - title = {Localization of {Kv1}.1 and {Kv1}.2, two {K} channel proteins, to synaptic terminals, somata, and dendrites in the mouse brain}, - year = {1994}, - issn = {0270-6474, 1529-2401}, - month = aug, - number = {8}, - pages = {4588--4599}, - volume = {14}, - abstract = {Multiple voltage-gated potassium (K) channel gene products are likely to be involved in regulating neuronal excitability of any single neuron in the mammalian brain. Here we show that two closely related voltage- gated K channel proteins, mKv1.1 and mKv1.2, are present in multiple subcellular locations including cell somata, juxta-paranodal regions of myelinated axons, synaptic terminals, unmyelinated axons, specialized junctions among axons, and proximal dendrites. Staining patterns of the two channel polypeptides overlap in some areas of the brain, yet each has a unique pattern of expression. For example, in the hippocampus, both mKv1.1 and mKv1.2 proteins are present in axons, often near or at synaptic terminals in the middle molecular layer of the dentate gyrus, while only mKv1.1 is detected in axons and synaptic terminals in the hilar/CA3 region. In the cerebellum, both channel proteins are localized to axon terminals and specialized junctions among axons in the plexus region of basket cells. Strong differential staining is observed in the olfactory bulb, where mKv1.2 is localized to cell somata and axons, as well as to proximal dendrites of the mitral cells. This overlapping yet differential pattern of expression and specific subcellular localization may contribute to the unique profile of excitability displayed by a particular neuron.}, - copyright = {© 1994 by Society for Neuroscience}, - doi = {10.1523/JNEUROSCI.14-08-04588.1994}, - file = {Full Text PDF:C\:/Users/nilsk/Zotero/storage/8W3QSPJ8/Wang et al. - 1994 - Localization of Kv1.1 and Kv1.2, two K channel pro.pdf:application/pdf;Snapshot:C\:/Users/nilsk/Zotero/storage/XW29S3YF/4588.html:text/html}, - language = {english}, - urldate = {2021-06-10}, -} - -@Article{carbone_ion_2020, - author = {Carbone, Emilio and Mori, Yasuo}, - journal = {Pflügers Archiv - European Journal of Physiology}, - title = {Ion channelopathies to bridge molecular lesions, channel function, and clinical therapies}, - year = {2020}, - issn = {1432-2013}, - month = jul, - number = {7}, - pages = {733--738}, - volume = {472}, - doi = {10.1007/s00424-020-02424-y}, - file = {Springer Full Text PDF:C\:/Users/nilsk/Zotero/storage/Z33W8XFN/Carbone and Mori - 2020 - Ion channelopathies to bridge molecular lesions, c.pdf:application/pdf}, - language = {english}, - urldate = {2021-07-27}, -} - - - -@Article{Scalmani2006, - author = {Scalmani, Paolo and Rusconi, Raffaella and Armatura, Elena and Zara, Federico and Avanzini, Giuliano and Franceschetti, Silvana and Mantegazza, Massimo}, - journal = {The Journal of Neuroscience}, - title = {Effects in {Neocortical} {Neurons} of {Mutations} of the {Nav1}.2 {Na}+ {Channel} causing {Benign} {Familial} {Neonatal}-{Infantile} {Seizures}}, - year = {2006}, - issn = {0270-6474}, - month = oct, - number = {40}, - pages = {10100--10109}, - volume = {26}, - abstract = {Mutations of voltage-gated Na+ channels are the most common cause of familial epilepsy. Benign familial neonatal-infantile seizures (BFNIS) is an epileptic trait of the early infancy, and it is the only well characterized epileptic syndrome caused exclusively by mutations of Nav1.2 Na+ channels, but no functional studies of BFNIS mutations have been done. The comparative study of the functional effects and the elucidation of the pathogenic mechanisms of epileptogenic mutations is essential for designing targeted and effective therapies. However, the functional properties of Na+ channels and the effects of their mutations are very sensitive to the cell background and thus to the expression system used. We investigated the functional effects of four of the six BFNIS mutations identified (L1330F, L1563V, R223Q, and R1319Q) using as expression system transfected pyramidal and bipolar neocortical neurons in short primary cultures, which have small endogenous Na+ current and thus permit the selective study of transfected channels. The mutation L1330F caused a positive shift of the inactivation curve, and the mutation L1563V caused a negative shift of the activation curve, effects that are consistent with neuronal hyperexcitability. The mutations R223Q and R1319Q mainly caused positive shifts of both activation and inactivation curves, effects that cannot be directly associated with a specific modification of excitability. Using physiological stimuli in voltage-clamp experiments, we showed that these mutations increase both subthreshold and action Na+ currents, consistently with hyperexcitability. Thus, the pathogenic mechanism of BFNIS mutations is neuronal hyperexcitability caused by increased Na+ current.}, - doi = {10.1523/JNEUROSCI.2476-06.2006}, - groups = {Jan}, - pmcid = {PMC6674637}, - pmid = {17021166}, - urldate = {2022-04-03}, -} - -@Article{shi_efficacy_2016, - author = {Shi, Xiu-Yu and Tomonoh, Yuko and Wang, Wen-Ze and Ishii, Atsushi and Higurashi, Norimichi and Kurahashi, Hirokazu and Kaneko, Sunao and Hirose, Shinichi and {Epilepsy Genetic Study Group, Japan}}, - title = {Efficacy of antiepileptic drugs for the treatment of {Dravet} syndrome with different genotypes}, - doi = {10.1016/j.braindev.2015.06.008}, - issn = {1872-7131}, - language = {english}, - number = {1}, - pages = {40--46}, - volume = {38}, - abstract = {OBJECTIVE: Evaluation of the efficacy of antiepileptic drugs (AEDs) used in the treatment of Dravet syndrome (DS) with different genotypes. -METHODS: Patients with DS were recruited from different tertiary hospitals. Using a direct sequencing method and Multiplex Ligation-Dependent Probe Amplification (MLPA), genetic abnormalities were assessed within the exons and flanking introns of SCN1A gene, which encodes the α1 subunit of neuronal sodium channels. Patients were divided into SCN1A-positive and SCN1A-negative groups according to the results of genetic tests. Medical records, including detailed treatment information, were surveyed to compare the effect of different AEDs on clonic or tonic-clonic seizures (GTCS). Efficacy variable was responder rate with regard to seizure reduction. -RESULTS: One hundred and sixty of 276 (57.97\%) patients had mutation in SCN1A gene (only 128 of them had provided detailed medical records). Among the 116 patients without SCN1A mutations, 87 had provided detailed medical records. Both older AEDs (valproate, phenobarbital, bromide, carbamazepine, clonazepam, and clobazam) and newer AEDs such as zonisamide were used in these patients. Valproate was the most frequently used AED (86.72\% in the SCN1A-positive group, 78.16\% in the SCN1A-negative group), with 52.25\% and 41.18\% responder rates in SCN1A-positive and SCN1A-negative patients, respectively (P=0.15). Bromide was used in 40.63\% of the SCN1A-positive patients and 20.69\% of the SCN1A-negative patients, and its responder rates were 71.15\% and 94.44\% in SCN1A-positive and SCN1A-negative patients, respectively (P=0.05). Efficacy rates of clonazepam, clobazam, phenobarbital, and zonisamide ranged from 30\% to 50\%, and these rates were not correlated with different genotypes (P{\textgreater}0.05). Carbamazepine had either no effect or aggravated seizures in all SCN1A-positive patients. -SIGNIFICANCE: Bromide is most effective and is a well-tolerated drug among DS patients, especially among SCN1A-negative patients. Carbamazepine should be avoided in patients with SCN1A mutations.}, - journal = {Brain \& Development}, - keywords = {Seizures, Male, Humans, Female, Adult, Young Adult, Adolescent, Child, Preschool, Infant, Treatment Outcome, Carbamazepine, Anticonvulsants, Mutation, Retrospective Studies, Antiepileptic drug therapy, Bromides, Dravet syndrome, Efficacy, Epilepsies, Myoclonic, Genetic tests, Genotype, Genotyping Techniques, NAV1.1 Voltage-Gated Sodium Channel}, - month = jan, - year = {2016}, -} - -@Article{soofi_co-variation_2012, - author = {Soofi, Wafa and Archila, Santiago and Prinz, Astrid A.}, - journal = {Journal of Computational Neuroscience}, - title = {Co-variation of ionic conductances supports phase maintenance in stomatogastric neurons}, - year = {2012}, - issn = {1573-6873}, - month = aug, - number = {1}, - pages = {77--95}, - volume = {33}, - abstract = {Neuronal networks produce reliable functional output throughout the lifespan of an animal despite ceaseless molecular turnover and a constantly changing environment. Central pattern generators, such as those of the crustacean stomatogastric ganglion (STG), are able to robustly maintain their functionality over a wide range of burst periods. Previous experimental work involving extracellular recordings of the pyloric pattern of the STG has demonstrated that as the burst period varies, the inter-neuronal delays are altered proportionally, resulting in burst phases that are roughly invariant. The question whether spike delays within bursts are also proportional to pyloric period has not been explored in detail. The mechanism by which the pyloric neurons accomplish phase maintenance is currently not obvious. Previous studies suggest that the co-regulation of certain ion channel properties may play a role in governing neuronal activity. Here, we observed in long-term recordings of the pyloric rhythm that spike delays can vary proportionally with burst period, so that spike phase is maintained. We then used a conductance-based model neuron to determine whether co-varying ionic membrane conductances results in neural output that emulates the experimentally observed phenomenon of spike phase maintenance. Next, we utilized a model neuron database to determine whether conductance correlations exist in model neuron populations with highly maintained spike phases. We found that co-varying certain conductances, including the sodium and transient calcium conductance pair, causes the model neuron to maintain a specific spike phase pattern. Results indicate a possible relationship between conductance co-regulation and phase maintenance in STG neurons.}, - doi = {10.1007/s10827-011-0375-3}, - file = {Springer Full Text PDF:C\:/Users/nilsk/Zotero/storage/6Q9T34AC/Soofi et al. - 2012 - Co-variation of ionic conductances supports phase .pdf:application/pdf}, - language = {english}, - urldate = {2021-07-01}, -} - - -@Article{Liu2019, - author = {Liu, Yuanyuan and Schubert, Julian and Sonnenberg, Lukas and Helbig, Katherine L and Hoei-Hansen, Christina E and Koko, Mahmoud and Rannap, Maert and Lauxmann, Stephan and Huq, Mahbubul and Schneider, Michael C and Johannesen, Katrine M and Kurlemann, Gerhard and Gardella, Elena and Becker, Felicitas and Weber, Yvonne G and Benda, Jan and Møller, Rikke S and Lerche, Holger}, - journal = {Brain}, - title = {Neuronal mechanisms of mutations in {SCN8A} causing epilepsy or intellectual disability}, - year = {2019}, - issn = {0006-8950}, - month = feb, - number = {2}, - pages = {376--390}, - volume = {142}, - abstract = {Ion channel mutations can cause distinct neuropsychiatric diseases. We first studied the biophysical and neurophysiological consequences of four mutations in the human Na+ channel gene SCN8A causing either mild (E1483K) or severe epilepsy (R1872W), or intellectual disability and autism without epilepsy (R1620L, A1622D). Only combined electrophysiological recordings of transfected wild-type or mutant channels in both neuroblastoma cells and primary cultured neurons revealed clear genotype–phenotype correlations. The E1483K mutation causing mild epilepsy showed no significant biophysical changes, whereas the R1872W mutation causing severe epilepsy induced clear gain-of-function biophysical changes in neuroblastoma cells. However, both mutations increased neuronal firing in primary neuronal cultures. In contrast, the R1620L mutation associated with intellectual disability and autism—but not epilepsy—reduced Na+ current density in neuroblastoma cells and expectedly decreased neuronal firing. Interestingly, for the fourth mutation, A1622D, causing severe intellectual disability and autism without epilepsy, we observed a dramatic slowing of fast inactivation in neuroblastoma cells, which induced a depolarization block in neurons with a reduction of neuronal firing. This latter finding was corroborated by computational modelling. In a second series of experiments, we recorded three more mutations (G1475R, M1760I, G964R, causing intermediate or severe epilepsy, or intellectual disability without epilepsy, respectively) that revealed similar results confirming clear genotype–phenotype relationships. We found intermediate or severe gain-of-function biophysical changes and increases in neuronal firing for the two epilepsy-causing mutations and decreased firing for the loss-of-function mutation causing intellectual disability. We conclude that studies in neurons are crucial to understand disease mechanisms, which here indicate that increased or decreased neuronal firing is responsible for distinct clinical phenotypes.}, - doi = {10.1093/brain/awy326}, - file = {:Liu2019 - Neuronal Mechanisms of Mutations in SCN8A Causing Epilepsy or Intellectual Disability.pdf:PDF}, - groups = {Jan}, - urldate = {2022-04-03}, -} - -@Article{bernard_channelopathies_2008, - author = {Bernard, Genevieve and Shevell, Michael I.}, - journal = {Pediatric Neurology}, - title = {Channelopathies: {A} {Review}}, - year = {2008}, - issn = {0887-8994}, - month = feb, - number = {2}, - pages = {73--85}, - volume = {38}, - abstract = {Channelopathies are a recently delineated, emerging group of neurologic disorders united by genetically determined defects in ion-channel function. These disorders are characterized by a prominent genetic and phenotypic heterogeneity that can make them challenging and bewildering to understand. This systematic review attempts to categorize these disorders according to their predominant clinical manifestations (i.e., myotonia, weakness, migraine, ataxia, epilepsy, and movement disorders) within the context of what is presently known about the molecular basis of recognized clinical syndromes. Areas of both genetic and phenotypic overlap are highlighted. The review is intended to assist clinicians in enhancing their diagnostic acumen and in targeting specific genetic tests.}, - doi = {10.1016/j.pediatrneurol.2007.09.007}, - file = {ScienceDirect Full Text PDF:C\:/Users/nilsk/Zotero/storage/MH4R3N5F/Bernard and Shevell - 2008 - Channelopathies A Review.pdf:application/pdf;ScienceDirect Snapshot:C\:/Users/nilsk/Zotero/storage/VED5EHSZ/S0887899407004584.html:text/html}, - language = {english}, - shorttitle = {Channelopathies}, - urldate = {2021-07-27}, -} - -@Article{stuhmer_molecular_1989, - author = {Stühmer, W. and Ruppersberg, J.p. and Schröter, K.h. and Sakmann, B. and Stocker, M. and Giese, K.p. and Perschke, A. and Baumann, A. and Pongs, O.}, - journal = {The EMBO Journal}, - title = {Molecular basis of functional diversity of voltage-gated potassium channels in mammalian brain.}, - year = {1989}, - issn = {0261-4189}, - month = nov, - number = {11}, - pages = {3235--3244}, - volume = {8}, - abstract = {Cloning and sequencing of cDNAs isolated from a rat cortex cDNA library reveals that a gene family encodes several highly homologous K+ channel forming (RCK) proteins. Functional characterization of the channels expressed in Xenopus laevis oocytes following microinjection of in vitro transcribed RCK-specific RNAs shows that each of the RCK proteins forms K+ channels that differ greatly in both their functional and pharmacological properties. This suggests that the molecular basis for the diversity of voltage-gated K+ channels in mammalian brain is based, at least partly, on the expression of several RCK proteins by a family of genes and their assembly to homooligomeric K+ channels with different functional properties.}, - doi = {10.1002/j.1460-2075.1989.tb08483.x}, - file = {Full Text:C\:/Users/nilsk/Zotero/storage/T4DRXSVK/Stühmer et al. - 1989 - Molecular basis of functional diversity of voltage.pdf:application/pdf;Snapshot:C\:/Users/nilsk/Zotero/storage/T22LZI5H/j.1460-2075.1989.tb08483.html:text/html}, - urldate = {2021-06-07}, -} - -@Article{jen_primary_2007, - author = {Jen, J.C. and Graves, T.D. and Hess, E.J. and Hanna, M.G. and Griggs, R.C. and Baloh, R.W. and {the CINCH investigators}}, - journal = {Brain}, - title = {Primary episodic ataxias: diagnosis, pathogenesis and treatment}, - year = {2007}, - issn = {0006-8950}, - month = oct, - number = {10}, - pages = {2484--2493}, - volume = {130}, - abstract = {Primary episodic ataxias are autosomal dominant channelopathies that manifest as attacks of imbalance and incoordination. Mutations in two genes, KCNA1 and CACNA1A, cause the best characterized and account for the majority of identified cases of episodic ataxia. We summarize current knowledge of clinical and genetic diagnosis, genotype–phenotype correlations, pathophysiology and treatment of episodic ataxia syndromes. We focus on unresolved issues including phenotypic and genetic heterogeneity, lessons from animal models and technological advancement, rationale and feasibility of various treatment strategies, and shared mechanisms underlying episodic ataxia and other far more prevalent paroxysmal conditions such as epilepsy and migraine.}, - doi = {10.1093/brain/awm126}, - file = {Full Text PDF:C\:/Users/nilsk/Zotero/storage/7VS52FIB/Jen et al. - 2007 - Primary episodic ataxias diagnosis, pathogenesis .pdf:application/pdf;Full Text PDF:C\:/Users/nilsk/Zotero/storage/STLLRYY4/Jen et al. - 2007 - Primary episodic ataxias diagnosis, pathogenesis .pdf:application/pdf;Snapshot:C\:/Users/nilsk/Zotero/storage/WWTFDAFS/372064.html:text/html;Snapshot:C\:/Users/nilsk/Zotero/storage/G7MY4DE3/372064.html:text/html}, - shorttitle = {Primary episodic ataxias}, - urldate = {2021-06-10}, -} - -@Article{coleman_subunit_1999, - author = {Coleman, Sarah K. and Newcombe, Jia and Pryke, Jonathan and Dolly, J. Oliver}, - journal = {Journal of Neurochemistry}, - title = {Subunit {Composition} of {Kv1} {Channels} in {Human} {CNS}}, - year = {1999}, - issn = {1471-4159}, - number = {2}, - pages = {849--858}, - volume = {73}, - abstract = {: The α subunits of Shaker-related K+ channels (Kv1.X) show characteristic distributions in mammalian brain and restricted coassembly. Despite the functional importance of these voltage-sensitive K+ channels and involvement in a number of diseases, little progress has been achieved in deciphering the subunit composition of the (α)4(β)4 oligomers occurring in human CNS. Thus, the association of α and β subunits was investigated in cerebral grey and white matter and spinal cord from autopsy samples. Immunoblotting established the presence of Kv1.1, 1.2, and 1.4 in all the tissues, with varying abundance. Sequential immunoprecipitations identified the subunits coassembled. A putative tetramer of Kv1.3/1.4/1.1/1.2 was found in grey matter. Both cerebral white matter and spinal cord contained the heterooligomers Kv1.1/1.4 and Kv1.1/1.2, similar to grey matter, but both lacked Kv1.3 and the Kv1.4/1.2 combination. An apparent Kv1.4 homooligomer was detected in all the samples, whereas only the brain tissue possessed a putative Kv1.2 homomer. In grey matter, Kvβ2.1 was coassociated with the Kv1.1/1.2 combination and Kv1.2 homooligomer. In white matter, Kvβ2.1 was associated with Kv1.2 only, whereas Kvβ1.1 coprecipitated with all the α subunits present. This represents the first description of Kv1 subunit complexes in the human CNS and demonstrates regional variations, indicative of functional specialisation.}, - doi = {10.1046/j.1471-4159.1999.0730849.x}, - file = {Full Text PDF:C\:/Users/nilsk/Zotero/storage/9N6K9G2L/Coleman et al. - 1999 - Subunit Composition of Kv1 Channels in Human CNS.pdf:application/pdf;Snapshot:C\:/Users/nilsk/Zotero/storage/54GLRDQU/j.1471-4159.1999.0730849.html:text/html}, - keywords = {Human, Potassium channel, Axolemma, CNS, Delayed rectifier, Immunoprecipitation.}, - language = {english}, - urldate = {2021-06-12}, -} - - - -@Article{Rush2006, - author = {Rush, Anthony M. and Dib-Hajj, Sulayman D. and Liu, Shujun and Cummins, Theodore R. and Black, Joel A. and Waxman, Stephen G.}, - journal = {Proceedings of the National Academy of Sciences}, - title = {A single sodium channel mutation produces hyper- or hypoexcitability in different types of neurons}, - year = {2006}, - month = may, - number = {21}, - pages = {8245--8250}, - volume = {103}, - doi = {10.1073/pnas.0602813103}, - groups = {Jan}, - publisher = {Proceedings of the National Academy of Sciences}, - urldate = {2022-03-05}, -} - -@Article{zuberi_novel_1999, - author = {Zuberi, S. M. and Eunson, L. H. and Spauschus, A. and De Silva, R. and Tolmie, J. and Wood, N. W. and McWilliam, R. C. and Stephenson, J. P. B. and Kullmann, D. M. and Hanna, M. G.}, - journal = {Brain}, - title = {A novel mutation in the human voltage-gated potassium channel gene ({Kv1}.1) associates with episodic ataxia type 1 and sometimes with partial epilepsy}, - year = {1999}, - issn = {0006-8950}, - month = may, - number = {5}, - pages = {817--825}, - volume = {122}, - abstract = {Episodic ataxia type 1 (EA1) is a rare autosomal dominant disorder characterized by brief episodes of ataxia associated with continuous interattack myokymia. Point mutations in the human voltage-gated potassium channel (Kv1.1) gene on chromosome 12p13 have recently been shown to associate with EA1. A Scottish family with EA1 harbouring a novel mutation in this gene is reported. Of the five affected individuals over three generations, two had partial epilepsy in addition to EA1. The detailed clinical, electrophysiological and molecular genetic findings are presented. The heterozygous point mutation is located at nucleotide position 677 and results in a radical amino acid substitution at a highly conserved position in the second transmembrane domain of the potassium channel. Functional studies indicated that mutant subunits exhibited a dominant negative effect on potassium channel function and would be predicted to impair neuronal repolarization. Potassium channels determine the excitability of neurons and blocking drugs are proconvulsant. A critical review of previously reported EA1 families shows an over-representation of epilepsy in family members with EA1 compared with unaffected members. These observations indicate that this mutation is pathogenic and suggest that the epilepsy in EA1 may be caused by the dysfunctional potassium channel. It is possible that such dysfunction may be relevant to other epilepsies in man.}, - doi = {10.1093/brain/122.5.817}, - file = {Full Text PDF:C\:/Users/nilsk/Zotero/storage/SEX9BDH8/Zuberi et al. - 1999 - A novel mutation in the human voltage-gated potass.pdf:application/pdf;Snapshot:C\:/Users/nilsk/Zotero/storage/Q6HMRVKV/296621.html:text/html;Snapshot:C\:/Users/nilsk/Zotero/storage/Y5C7TN83/296621.html:text/html}, - urldate = {2021-06-10}, -} - -@Article{rajakulendran_episodic_2007, - author = {Rajakulendran, Sanjeev and Schorge, Stephanie and Kullmann, Dimitri M. and Hanna, Michael G.}, - journal = {Neurotherapeutics}, - title = {Episodic ataxia type 1: {A} neuronal potassium channelopathy}, - year = {2007}, - issn = {1878-7479}, - month = apr, - number = {2}, - pages = {258--266}, - volume = {4}, - abstract = {Episodic ataxia type 1 is a paroxysmal neurological disorder characterized by short-lived attacks of recurrent midline cerebellar dysfunction and continuous motor activity. Mutations in KCN1A, the gene encoding Kv1.1, a voltage-gated neuronal potassium channel, are associated with the disorder. Although rare, the syndrome highlights the fundamental features of genetic ion-channel diseases and serves as a useful model for understanding more common paroxysmal disorders, such as epilepsy and migraine. This review examines our current understanding of episodic ataxia type 1, focusing on its clinical and genetic features, pathophysiology, and treatment.}, - doi = {10.1016/j.nurt.2007.01.010}, - file = {Springer Full Text PDF:C\:/Users/nilsk/Zotero/storage/TCNZXIXP/Rajakulendran et al. - 2007 - Episodic ataxia type 1 A neuronal potassium chann.pdf:application/pdf}, - language = {english}, - shorttitle = {Episodic ataxia type 1}, - urldate = {2021-06-10}, -} - -@Article{ponce_expression_2018, - author = {Ponce, Arturo and Castillo, Aida and Hinojosa, Lorena and Martinez‐Rendon, Jacqueline and Cereijido, Marcelino}, - journal = {Physiological Reports}, - title = {The expression of endogenous voltage‐gated potassium channels in {HEK293} cells is affected by culture conditions}, - year = {2018}, - issn = {2051-817X}, - month = apr, - number = {8}, - pages = {e13663}, - volume = {6}, - abstract = {HEK293 cells are widely used as a host for expression of heterologous proteins; yet, little care has been taken to characterize their endogenous membrane components, including ion channels. In this work, we aimed to describe the biophysical and pharmacological properties of endogenous, voltage‐dependent potassium currents (IKv). We also examined how its expression depends on culture conditions. We used the electrophysiological technique of whole‐cell patch clamp to record ion currents from HEK293 cells. We found that HEK cells express endogenous, voltage‐dependent potassium currents. We also found that diverse culture conditions, such as the passage number, the cell density, the type of serum that complements the culture media and the substratum, affect the magnitude and shape of IKv, resulting from the relative contribution of fast, slow, and noninactivating component currents. Incubation of cells in mature monolayers with trypsin–EDTA, notoriously reduces the magnitude and modifies the shape of voltage‐dependent potassium endogenous currents; nonetheless HEK cells recover IKv′s magnitude and shape within 6 h after replating, with a process that requires synthesis of new mRNA and protein subunits, as evidenced by the fact that actinomycin D and cycloheximide, inhibitors of synthesis of mRNA and protein, respectively, impair the recovery of IKv after trypsinization. In addition to be useful as a model expression system, HEK293 may be useful to understand how cells regulate the density of ion channels on the membrane.}, - doi = {10.14814/phy2.13663}, - file = {PubMed Central Full Text PDF:C\:/Users/nilsk/Zotero/storage/3EW2NAWL/Ponce et al. - 2018 - The expression of endogenous voltage‐gated potassi.pdf:application/pdf}, - pmcid = {PMC5903699}, - pmid = {29665277}, - urldate = {2021-07-28}, -} - -@Article{rutecki_neuronal_1992, - author = {Rutecki, P. A.}, - title = {Neuronal excitability: voltage-dependent currents and synaptic transmission}, - issn = {0736-0258}, - language = {english}, - number = {2}, - pages = {195--211}, - volume = {9}, - abstract = {Neuronal membrane excitability and the synaptic connections among neurons produce behavior and cognition. The intracellular compartment of neurons is negatively charged relative to the extracellular space, and this charge, as well as current flow, is produced by ions. From the perspective of charged ions, the lipid bilayer of the neuronal membrane acts as a capacitor, and transmembrane glycoprotein pores or channels act as resistors. The open and closed states of ionic channels determine the membrane potential. At equilibrium, the lowest resistance or greatest permeability is for potassium, and the resting membrane potential is close to the equilibrium potential for potassium. When a channel is opened, permeable ions diffuse down their electrochemical gradients and the membrane potential is changed. Channels are gated (opened or closed) by voltage, neurotransmitters, and second messengers. The neuron integrates synaptic potentials produced by transmitter-gated channel activity and either generates a subthreshold potential, or a suprathreshold depolarization that generates an action potential or a burst of action potentials. Action potential generation is mediated by a large, brief sodium influx that is followed by activation of a voltage-dependent potassium eflux. The pattern of action potential firing is dependent on the interaction of a repertoire of voltage-dependent ion conductances. The action potential is the main signaling mechanism to activate synaptic transmission at axon terminals. Synaptic transmission is graded depending on the amount of calcium entering the presynaptic terminal. The number of action potentials, or the shape of the action potential, will determine the amount of calcium entering the terminal and the efficacy of synaptic transmission. Presynaptic ion channels may also be controlled by neurotransmitters or modulators and affect synaptic transmission by altering the amount of calcium influx.}, - journal = {Journal of Clinical Neurophysiology: Official Publication of the American Electroencephalographic Society}, - keywords = {Animals, Synapses, Membrane Potentials, Synaptic Transmission, Humans, Axons, Central Nervous System, Dendrites, Ion Channels, Neuromuscular Junction, Neurotransmitter Agents, Synaptic Membranes}, - month = apr, - shorttitle = {Neuronal excitability}, - year = {1992}, -} - -@Article{czitrom_one-factor-at--time_1999, - author = {Czitrom, Veronica}, - journal = {The American Statistician}, - title = {One-{Factor}-at-a-{Time} versus {Designed} {Experiments}}, - year = {1999}, - issn = {0003-1305}, - number = {2}, - pages = {126--131}, - volume = {53}, - abstract = {Many engineers and scientists perform one-factor-at-a-time (OFAT) experiments. They will continue to do so until they understand the advantages of designed experiments over OFAT experiments, and until they learn to recognize OFAT experiments so they can avoid them. A very effective way to illustrate the advantages of designed experiments, and to show ways in which OFAT experiments present themselves in real life, is to introduce real examples of OFAT experiments and then demonstrate why a designed experiment would have been better. Three engineering examples of OFAT experiments are presented, as well as designed experiments that would have been better. The three examples have been successfully used in an industrial workshop and can also be used in academic courses.}, - doi = {10.2307/2685731}, - file = {Submitted Version:C\:/Users/nilsk/Zotero/storage/GW8BJJXX/Czitrom - 1999 - One-Factor-at-a-Time versus Designed Experiments.pdf:application/pdf}, - urldate = {2021-06-02}, -} - -@Article{van_dyke_hereditary_1975, - author = {Van Dyke, D. H. and Griggs, R. C. and Murphy, M. J. and Goldstein, M. N.}, - journal = {Journal of the Neurological Sciences}, - title = {Hereditary myokymia and periodic ataxia}, - year = {1975}, - issn = {0022-510X}, - month = may, - number = {1}, - pages = {109--118}, - volume = {25}, - abstract = {A kindred in which at least 11 individuals in 3 consecutive generations have continuous muscle movement, i.e., myokymia, and periodic ataxia, has been studied. Three patients, a 24-year-old woman, her 4-year-old son and her 27-year-old sister, have been studied in detail. The disorder is inherited as an autosomal-dominant trait and presents in early childhood with attacks of ataxia of 1–2 min in duration, with associated jerking movements of the head, arms and legs. Attacks are provoked by abrupt postural change, emotional stimulus, and caloric-vestibular stimulation. At the age of 12 years approximately, facial and extremity myokymia appears. Physical findings include large calves, normal muscle strength and widespread myokymia of face, hands, arms and legs with a hand posture resembling carpopedal spasm. EMG studies at rest showed continuous spontaneous activity of otherwise normal motor units. Nerve conduction velocities were normal. Gastrocnemius biopsy in 2 patients showed fiber type grouping and small angular fibers, and was consistent with denervation. Histographic analysis of the biopsies demonstrated enlargement of both fiber types, particularly of Type I fibers. These findings are consistent with chronic denervation and an abnormality of motor neuron population or firing. The myokymia described here is of interest not only because of its genetic association with a movement disorder, but also because the muscle findings support a peripheral basis for the muscle movements.}, - doi = {10.1016/0022-510X(75)90191-4}, - file = {ScienceDirect Full Text PDF:C\:/Users/nilsk/Zotero/storage/GZD6WJU6/Van Dyke et al. - 1975 - Hereditary myokymia and periodic ataxia.pdf:application/pdf;ScienceDirect Snapshot:C\:/Users/nilsk/Zotero/storage/XQD53H6D/0022510X75901914.html:text/html}, - language = {english}, - urldate = {2021-06-10}, -} - - - - -@Article{ermentrout_type_1996, - author = {Ermentrout, Bard}, - journal = {Neural Computation}, - title = {Type {I} {Membranes}, {Phase} {Resetting} {Curves}, and {Synchrony}}, - year = {1996}, - issn = {0899-7667}, - month = jul, - number = {5}, - pages = {979--1001}, - volume = {8}, - abstract = {Type I membrane oscillators such as the Connor model (Connor et al. 1977) and the Morris-Lecar model (Morris and Lecar 1981) admit very low frequency oscillations near the critical applied current. Hansel et al. (1995) have numerically shown that synchrony is difficult to achieve with these models and that the phase resetting curve is strictly positive. We use singular perturbation methods and averaging to show that this is a general property of Type I membrane models. We show in a limited sense that so called Type II resetting occurs with models that obtain rhythmicity via a Hopf bifurcation. We also show the differences between synapses that act rapidly and those that act slowly and derive a canonical form for the phase interactions.}, - doi = {10.1162/neco.1996.8.5.979}, -} - -@Article{tsaur_differential_1992, - author = {Tsaur, Meei-Ling and Sheng, Morgan and Lowenstein, Daniel H. and Jan, Yuh Nung and Jan, Lily Yeh}, - journal = {Neuron}, - title = {Differential expression of {K}+ channel {mRNAs} in the rat brain and down-regulation in the hippocampus following seizures}, - year = {1992}, - issn = {0896-6273}, - month = jun, - number = {6}, - pages = {1055--1067}, - volume = {8}, - abstract = {K+ channels are major determinants of membrane excitability. Differences in neuronal excitability within the nervous system may arise from differential expression of K+ channel genes, regulated spatially in a cell type-specific manner, or temporally in response to neuronal activity. We have compared the distribution of mRNAs of three K+ channel genes, Kv1.1, Kv1.2, and Kv4.2 in rat brain, and examined activity-dependent changes following treatment with the convulsant drug pentylenetetrazole. Both regional and cell type-specific differences of K+ channel gene expression were found. In addition, seizure activity caused a reduction of Kv1.2 and Kv4.2 mRNAs in the dentate granule cells of the hippocampus, raising the possibility that K+ channel gene regulation may play a role in long-term neuronal plasticity.}, - doi = {10.1016/0896-6273(92)90127-Y}, - file = {ScienceDirect Full Text PDF:C\:/Users/nilsk/Zotero/storage/AV3MLGZ2/Tsaur et al. - 1992 - Differential expression of K+ channel mRNAs in the.pdf:application/pdf;ScienceDirect Snapshot:C\:/Users/nilsk/Zotero/storage/BAQZSPTI/089662739290127Y.html:text/html}, - language = {english}, - urldate = {2021-06-12}, -} - -@Article{veh_immunohistochemical_1995, - author = {Veh, Rüdiger W. and Lichtinghagen, Ralf and Sewing, Sabine and Wunder, Frank and Grumbach, Isabella M. and Pongs, Olaf}, - journal = {European Journal of Neuroscience}, - title = {Immunohistochemical {Localization} of {Five} {Members} of the {KV1} {Channel} {Subunits}: {Contrasting} {Subcellular} {Locations} and {Neuron}-specific {Co}-localizations in {Rat} {Brain}}, - year = {1995}, - issn = {1460-9568}, - number = {11}, - pages = {2189--2205}, - volume = {7}, - abstract = {A large variety of potassium channels is involved in regulating integration and transmission of electrical signals in the nervous system. Different types of neurons, therefore, require specific patterns of potassium channel subunit expression and specific regulation of subunit coassembly into heteromultimeric channels, as well as subunit-specific sorting and segregation. This was investigated by studying in detail the expression of six different α-subunits of voltage-gated potassium channels in the rat hippocampus, cerebellum, olfactory bulb and spinal cord, combining in situ hybridization and immunocytochemistry. Specific polyclonal antibodies were prepared for five α-subunits (KV1.1, KV1.2, KV1.3, KV1.4, KV1.6) of the Shaker-related subfamily of rat Kv channels, which encode delayed-rectifier type and rapidly inactivating A-type potassium channels. Their distribution was compared to that of an A-type potassium channel (KV3.4), belonging to the Shaw-related subfamily of rat Kv channels. Our results show that these Kv channel α-subunits are differentially expressed in rat brain neurons. We did not observe in various neurons a stereotypical distribution of Kv channel α-subunits to dendritic and axonal compartments, but a complex differential subcellular subunit distribution. The different Kv channel subunits are targeted either to presynaptic or to postsynaptic domains, depending on neuronal cell type. Thus, distinct combinations of Kv1 α-subunits are co-localized in different neurons. The implications of these findings are that both differential expression and assembly as well as subcellular targeting of Kv channel α-subunits may contribute to Kv channel diversity and thereby to presynaptic and postsynaptic membrane excitability.}, - doi = {10.1111/j.1460-9568.1995.tb00641.x}, - file = {Full Text PDF:C\:/Users/nilsk/Zotero/storage/FBDVD9YW/Veh et al. - 1995 - Immunohistochemical Localization of Five Members o.pdf:application/pdf;Full Text PDF:C\:/Users/nilsk/Zotero/storage/2DYEMJUC/Veh et al. - 1995 - Immunohistochemical Localization of Five Members o.pdf:application/pdf;Snapshot:C\:/Users/nilsk/Zotero/storage/TCXWZH3V/j.1460-9568.1995.tb00641.html:text/html;Snapshot:C\:/Users/nilsk/Zotero/storage/CQNWEC4V/j.1460-9568.1995.tb00641.html:text/html}, - keywords = {potassium channels, hybridization, in situ, rat brain}, - language = {english}, - shorttitle = {Immunohistochemical {Localization} of {Five} {Members} of the {KV1} {Channel} {Subunits}}, - urldate = {2021-06-10}, -} - -@Article{brew_hyperexcitability_2003, - author = {Brew, Helen M. and Hallows, Janice L. and Tempel, Bruce L.}, - journal = {The Journal of Physiology}, - title = {Hyperexcitability and reduced low threshold potassium currents in auditory neurons of mice lacking the channel subunit {Kv1}.1}, - year = {2003}, - issn = {1469-7793}, - number = {1}, - pages = {1--20}, - volume = {548}, - abstract = {A low voltage-activated potassium current, IKL, is found in auditory neuron types that have low excitability and precisely preserve the temporal pattern of activity present in their presynaptic inputs. The gene Kcna1 codes for Kv1.1 potassium channel subunits, which combine in expression systems to produce channel tetramers with properties similar to those of IKL, including sensitivity to dendrotoxin (DTX). Kv1.1 is strongly expressed in neurons with IKL, including auditory neurons of the medial nucleus of the trapezoid body (MNTB). We therefore decided to investigate how the absence of Kv1.1 affected channel properties and function in MNTB neurons from mice lacking Kcna1. We used the whole cell version of the patch clamp technique to record from MNTB neurons in brainstem slices from Kcna1-null (−/−) mice and their wild-type (+/+) and heterozygous (+/−) littermates. There was an IKL in voltage-clamped −/− MNTB neurons, but it was about half the amplitude of the IKL in +/+ neurons, with otherwise similar properties. Consistent with this, −/− MNTB neurons were more excitable than their +/+ counterparts; they fired more than twice as many action potentials (APs) during current steps, and the threshold current amplitude required to generate an AP was roughly halved. +/− MNTB neurons had excitability and IKL amplitudes identical to the +/+ neurons. The IKL remaining in −/− neurons was blocked by DTX, suggesting the underlying channels contained subunits Kv1.2 and/or Kv1.6 (also DTX-sensitive). DTX increased excitability further in the already hyperexcitable −/− MNTB neurons, suggesting that −/−IKL limited excitability despite its reduced amplitude in the absence of Kv1.1 subunits.}, - copyright = {© 2003 The Journal of Physiology © 2003 The Physiological Society}, - doi = {10.1111/j..2003.t01-1-00001.x}, - file = {Full Text PDF:C\:/Users/nilsk/Zotero/storage/KHZTN5RA/Brew et al. - 2003 - Hyperexcitability and reduced low threshold potass.pdf:application/pdf;Snapshot:C\:/Users/nilsk/Zotero/storage/SRKME4BH/j..2003.t01-1-00001.html:text/html}, - language = {english}, - urldate = {2021-06-14}, -} - -@Article{isacoff_evidence_1990, - author = {Isacoff, Ehud Y. and Jan, Yuh Nung and Jan, Lily Yeh}, - journal = {Nature}, - title = {Evidence for the formation of heteromultimeric potassium channels in {Xenopus} oocytes}, - year = {1990}, - issn = {1476-4687}, - month = jun, - number = {6275}, - pages = {530--534}, - volume = {345}, - abstract = {POTASSIUM channels show a wide range of functional diversity1–3. Nerve cells typically express a number of K+. channels that differ in their kinetics, single-channel conductance, pharmacology, and sensitivity to voltage and second messengers. The cloning of the Shaker gene in Drosophila4–7, and of related genes8–14, has revealed that the encoded K+ channel polypeptides resemble one of the four internally homologous domains of the α-subunits of Na+ channels and Ca2+ channels15–18, indicating that K+ channels may form by the co-assembly of several polypeptides. In this report we provide evidence that the Shaker A-type K+ channels expressed in Xenopus oocytes contain several Shaker polypeptides, that heteromultimeric channels may form through assembly of different channel polypeptides, that the kinetics or pharmacology of some heteromultimeric channels differ from those of homomultimeric channels, and that channel polypeptides from the fruit fly can co-assemble with homologous polypeptides from the rat. We suggest that heteromultimer formation may increase K+ channel diversity beyond even the level expected from the large number of K+ channel genes and alternative splicing products4,5,19–25.}, - copyright = {1990 Nature Publishing Group}, - doi = {10.1038/345530a0}, - file = {Full Text PDF:C\:/Users/nilsk/Zotero/storage/7W7QWWF8/Isacoff et al. - 1990 - Evidence for the formation of heteromultimeric pot.pdf:application/pdf;Snapshot:C\:/Users/nilsk/Zotero/storage/4S7NC3QA/345530a0.html:text/html}, - language = {english}, - urldate = {2021-06-12}, -} - -@Article{roeper_nip_1998, - author = {Roeper, Jochen and Sewing, Sabine and Zhang, Ying and Sommer, Tobias and Wanner, Siegmund G. and Pongs, Olaf}, - journal = {Nature}, - title = {{NIP} domain prevents {N}-type inactivation in voltage-gated potassium channels}, - year = {1998}, - issn = {1476-4687}, - month = jan, - number = {6665}, - pages = {390--393}, - volume = {391}, - abstract = {Shaker-related voltage-gated K+ (Kv) channels1,2 are assembled from ion-conducting Kvα subunits, which are integral membrane proteins, and auxiliary Kvβ subunits. This leads to the formation of highly diverse heteromultimeric Kv channels that mediate outward currents with a wide range of time courses for inactivation. Two principal inactivation mechanisms have been recognized1: C-type inactivation correlated with carboxy-terminal Kvα-subunit structures3, and N-type inactivation conferred by ‘ball’ domains in the amino termini of certain Kvα4,5 and Kvβ6 subunits. Assembly of heteromultimers with one or more Kvα4,7- and/or Kvβ6 ball domains appears to be an essential principle of the generation of A-type Kv channel diversity. Here we show that, unexpectedly, the presence of Kvα- or Kvβ-ball domains does not dominate the gating phenotype in heteromultimers containing Kv1.6α subunits. These heteromultimers mediate non-inactivating currents because of the dominant-negative activity of a new type of N-type inactivation-prevention (NIP) domain present in the Kv1.6 amino terminus. Mutations in the NIP domain lead to loss of function, and its transfer to another Kvα subunit leads to gain of function. Our discovery of the NIP domain, which neutralizes the activity of Kvα- and Kvβ-inactivation gates, establishes a new determinant for the gating behaviour of heteromultimeric Kv channels.}, - copyright = {1998 Macmillan Magazines Ltd.}, - doi = {10.1038/34916}, - file = {Full Text PDF:C\:/Users/nilsk/Zotero/storage/BPJPQVJA/Roeper et al. - 1998 - NIP domain prevents N-type inactivation in voltage.pdf:application/pdf;Snapshot:C\:/Users/nilsk/Zotero/storage/8V4C3VA2/34916.html:text/html}, - language = {english}, - urldate = {2021-06-07}, -} - -@Article{ransdell_neurons_2013, - author = {Ransdell, Joseph L. and Nair, Satish S. and Schulz, David J.}, - journal = {Journal of Neuroscience}, - title = {Neurons within the {Same} {Network} {Independently} {Achieve} {Conserved} {Output} by {Differentially} {Balancing} {Variable} {Conductance} {Magnitudes}}, - year = {2013}, - month = jun, - number = {24}, - pages = {9950--9956}, - volume = {33}, - file = {Neurons within the Same Network Independently Achieve Conserved Output by Differentially Balancing Variable Conductance Magnitudes | Journal of Neuroscience:C\:/Users/nilsk/Zotero/storage/YM4JHXV4/9950.html:text/html}, -} - -@Article{zhang_specific_1999, - author = {Zhang, Chuan-Li and Messing, Albee and Chiu, Shing Yan}, - journal = {Journal of Neuroscience}, - title = {Specific {Alteration} of {Spontaneous} {GABAergic} {Inhibition} in {Cerebellar} {Purkinje} {Cells} in {Mice} {Lacking} the {Potassium} {Channel} {Kv1}.1}, - year = {1999}, - issn = {0270-6474, 1529-2401}, - month = apr, - number = {8}, - pages = {2852--2864}, - volume = {19}, - abstract = {In the cerebellum, the basket cell innervation on Purkinje cells provides a major GABAergic inhibitory control of the single efferent output from the cerebellum. The Shaker-type K channel Kv1.1 is localized at the axon arborization preceding the terminal of the basket cells and is therefore a potential candidate for regulating the GABAergic inhibition. In this study, we directly assess this role of Kv1.1 by electrophysiological analysis of Kv1.1 null mutant mice. Whole-cell patch-clamp recordings of spontaneous IPSCs (sIPSCs) were made from Purkinje cells in thin cerebellar slices from postnatal day (P)10–15 Kv1.1-null mutants using wild-type littermates as controls. The null mutation confers a very specific change in the sIPSC: the frequency increases about twofold, without accompanying changes in the mean and variance of its amplitude distribution. The frequency and amplitude of the miniature IPSCs (mIPSCs) are unaffected. Spontaneous firing rate of the basket cells is unaltered. Evoked IPSC does not show multiple activity in the mutants. Motor skills tests show that Kv1.1 null mice display a compromised ability to maintain balance on a thin stationary rod. We conclude that the Kv1.1 null mutation results in a persistent elevation of the tonic inhibitory tone on the cerebellum Purkinje cell efferent and that this is not fully compensated for by residual Shaker-type channels. We further suggest that the increase in inhibitory tone in the mutants might underlie the behavioral deficits. At the cellular level, we propose that Kv1.1 deletion enhances excitability of the basket cells by selectively enhancing the likelihood of action potential propagation past axonal branch points.}, - copyright = {Copyright © 1999 Society for Neuroscience}, - doi = {10.1523/JNEUROSCI.19-08-02852.1999}, - file = {Full Text PDF:C\:/Users/nilsk/Zotero/storage/CAKAQZ6X/Zhang et al. - 1999 - Specific Alteration of Spontaneous GABAergic Inhib.pdf:application/pdf;Snapshot:C\:/Users/nilsk/Zotero/storage/8MH5FK92/2852.html:text/html}, - keywords = {mouse, GABA, cerebellum, Purkinje cell, homologous recombination, potassium channel gene}, - language = {english}, - urldate = {2021-06-10}, -} - -@Article{khaliq_relative_2006, - author = {Khaliq, Zayd M. and Raman, Indira M.}, - journal = {Journal of Neuroscience}, - title = {Relative {Contributions} of {Axonal} and {Somatic} {Na} {Channels} to {Action} {Potential} {Initiation} in {Cerebellar} {Purkinje} {Neurons}}, - year = {2006}, - month = feb, - number = {7}, - pages = {1935--1944}, - volume = {26}, - file = {Relative Contributions of Axonal and Somatic Na Channels to Action Potential Initiation in Cerebellar Purkinje Neurons | Journal of Neuroscience:C\:/Users/nilsk/Zotero/storage/A2ZU9LSD/1935.html:text/html}, -} - -@Article{otsuka_conductance-based_2004, - author = {Otsuka, Takeshi and Abe, Takafumi and Tsukagawa, Takahisa and Song, Wen-Jie}, - journal = {Journal of Neurophysiology}, - title = {Conductance-{Based} {Model} of the {Voltage}-{Dependent} {Generation} of a {Plateau} {Potential} in {Subthalamic} {Neurons}}, - year = {2004}, - issn = {0022-3077}, - month = jul, - number = {1}, - pages = {255--264}, - volume = {92}, - abstract = {Because the subthalamic nucleus (STN) acts as a driving force of the basal ganglia, it is important to know how the activities of STN neurons are regulated. Previously, we have reported that a subset of STN neurons generates a plateau potential in a voltage-dependent manner. These plateau potentials can be evoked only when the cell is hyperpolarized. Here, to examine the mechanism of the voltage-dependent generation of the plateau potential in STN neurons, we constructed a conductance-based model of the plateau-generating STN neuron based on experimental observations and compared simulation results with recordings in slices. The model consists of a single compartment containing a Na+ current, a delayed-rectifier K+ current, an A-type K+ current, an L-like long-lasting Ca2+ current, a T-type Ca2+ current, a Ca2+-dependent K+ current, and a leak current. Our simulation results showed that a plateau potential in the model could be induced in a voltage-dependent manner that depended on the inactivation properties of L-like long-lasting Ca2+ current. The model could also reproduce the generation of a plateau potential as a rebound potential after termination of hyperpolarizing current injection. In addition, we tested the stability of simulated plateau potentials against inhibitory perturbation and found that the model showed similar properties observed for the plateau potentials of STN neurons in slices. The effects of K+ channel blockade by TEA and intracellular Ca2+ ion chelation by BAPTA on the plateau duration were also tested in the model and were found to match experimental observations. Thus our STN neuron model could qualitatively reproduce a number of experimental observations on plateau potentials. Our results suggest that the inactivation of L-type Ca2+ channels plays an important role in the voltage-dependent generation of the plateau potential.}, - doi = {10.1152/jn.00508.2003}, - file = {Full Text PDF:C\:/Users/nilsk/Zotero/storage/YYMYAXMJ/Otsuka et al. - 2004 - Conductance-Based Model of the Voltage-Dependent G.pdf:application/pdf;Snapshot:C\:/Users/nilsk/Zotero/storage/NIZRIRNC/jn.00508.html:text/html}, - urldate = {2021-03-31}, -} - -@Article{zhou_temperature-sensitive_1998, - author = {Zhou, Lei and Zhang, Chuan-Li and Messing, Albee and Chiu, Shing Yan}, - journal = {Journal of Neuroscience}, - title = {Temperature-{Sensitive} {Neuromuscular} {Transmission} in {Kv1}.1 {Null} {Mice}: {Role} of {Potassium} {Channels} under the {Myelin} {Sheath} in {Young} {Nerves}}, - year = {1998}, - issn = {0270-6474, 1529-2401}, - month = sep, - number = {18}, - pages = {7200--7215}, - volume = {18}, - abstract = {In mammalian myelinated nerves, the internodal axon that is normally concealed by the myelin sheath expresses a rich repertoire of K channel subtypes thought to be important in modulating action potential propagation. The function of myelin-covered K channels at transition zones, however, has remained unexplored. Here we show that deleting the voltage-sensitive potassium channel Kv1.1 from mice confers a marked temperature-sensitivity to neuromuscular transmission in postnatal day 14 (P14)–P21 mice. Using immunofluorescence and electrophysiology, we examined contributions of four regions of the peripheral nervous system to the mutant phenotype: the nerve trunk, the myelinated segment preceding the terminal, the presynaptic terminal membrane itself, and the muscle. We conclude that the temperature-sensitive neuromuscular transmission is accounted for solely by a deficiency in Kv1.1 normally concealed in the myelinated segments just preceding the terminal. This paper demonstrates that under certain situations of physiological stress, the functional role of myelin-covered K channels is dramatically enhanced as the transition zone at the neuromuscular junction is approached.}, - copyright = {Copyright © 1998 Society for Neuroscience}, - doi = {10.1523/JNEUROSCI.18-18-07200.1998}, - file = {Full Text PDF:C\:/Users/nilsk/Zotero/storage/SCRRDKGM/Zhou et al. - 1998 - Temperature-Sensitive Neuromuscular Transmission i.pdf:application/pdf;Snapshot:C\:/Users/nilsk/Zotero/storage/FQBN6Q2X/7200.html:text/html}, - keywords = {mouse, end plate, homologous recombination, myelinated nerves, nerve conduction, potassium channel gene}, - language = {english}, - shorttitle = {Temperature-{Sensitive} {Neuromuscular} {Transmission} in {Kv1}.1 {Null} {Mice}}, - urldate = {2021-06-10}, -} - -@Article{xu_kv2_1997, - author = {Xu, Jia and Li, Min}, - journal = {Journal of Biological Chemistry}, - title = {Kvβ2 {Inhibits} the {Kvβ1}-mediated {Inactivation} of {K}+ {Channels} in {Transfected} {Mammalian} {Cells}}, - year = {1997}, - issn = {0021-9258}, - month = may, - number = {18}, - pages = {11728--11735}, - volume = {272}, - abstract = {Cloned auxiliary β-subunits (e.g.Kvβ1) modulate the kinetic properties of the pore-forming α-subunits of a subset of Shaker-like potassium channels. Coexpression of the α-subunit and Kvβ2, however, induces little change in channel properties. Since more than one β-subunit has been found in individual K+ channel complexes and expression patterns of different β-subunits overlap in vivo, it is important to test the possible physical and/or functional interaction(s) between different β-subunits. In this report, we show that both Kvβ2 and Kvβ1 recognize the same region on the pore-forming α-subunits of the Kv1 Shaker-like potassium channels. In the absence of α-subunits the Kvβ2 polypeptide interacts with additional β-subunit(s) to form either a homomultimer with Kvβ2 or a heteromultimer with Kvβ1. When coexpressing α-subunits and Kvβ1 in the presence of Kvβ2, we find that Kvβ2 is capable of inhibiting the Kvβ1-mediated inactivation. Using deletion analysis, we have localized the minimal interaction region that is sufficient for Kvβ2 to associate with both α-subunits and Kvβ1. This mapped minimal interaction region is necessary and sufficient for inhibiting the Kvβ1-mediated inactivation, consistent with the notion that the inhibitory activity of Kvβ2 results from the coassembly of Kvβ2 with compatible α-subunits and possibly with Kvβ1. Together, these results provide biochemical evidence that Kvβ2 may profoundly alter the inactivation activity of another β-subunit by either differential subunit assembly or by competing for binding sites on α-subunits, which indicates that Kvβ2 is capable of serving as an important determinant in regulating the kinetic properties of K+currents.}, - doi = {10.1074/jbc.272.18.11728}, - file = {ScienceDirect Full Text PDF:C\:/Users/nilsk/Zotero/storage/RVNNHGE9/Xu and Li - 1997 - Kvβ2 Inhibits the Kvβ1-mediated Inactivation of K+.pdf:application/pdf;ScienceDirect Snapshot:C\:/Users/nilsk/Zotero/storage/EG8EMIEK/S0021925818405091.html:text/html}, - language = {english}, - urldate = {2021-06-12}, -} - - -@Article{Gnecchi2021, - author = {Gnecchi, Massimiliano and Sala, Luca and Schwartz, Peter J}, - journal = {European Heart Journal}, - title = {Precision {Medicine} and cardiac channelopathies: when dreams meet reality}, - year = {2021}, - issn = {0195-668X}, - month = may, - number = {17}, - pages = {1661--1675}, - volume = {42}, - abstract = {Precision Medicine (PM) is an innovative approach that, by relying on large populations’ datasets, patients’ genetics and characteristics, and advanced technologies, aims at improving risk stratification and at identifying patient-specific management through targeted diagnostic and therapeutic strategies. Cardiac channelopathies are being progressively involved in the evolution brought by PM and some of them are benefiting from these novel approaches, especially the long QT syndrome. Here, we have explored the main layers that should be considered when developing a PM approach for cardiac channelopathies, with a focus on modern in vitro strategies based on patient-specific human-induced pluripotent stem cells and on in silico models. PM is where scientists and clinicians must meet and integrate their expertise to improve medical care in an innovative way but without losing common sense. We have indeed tried to provide the cardiologist’s point of view by comparing state-of-the-art techniques and approaches, including revolutionary discoveries, to current practice. This point matters because the new approaches may, or may not, exceed the efficacy and safety of established therapies. Thus, our own eagerness to implement the most recent translational strategies for cardiac channelopathies must be tempered by an objective assessment to verify whether the PM approaches are indeed making a difference for the patients. We believe that PM may shape the diagnosis and treatment of cardiac channelopathies for years to come. Nonetheless, its potential superiority over standard therapies should be constantly monitored and assessed before translating intellectually rewarding new discoveries into clinical practice.}, - doi = {10.1093/eurheartj/ehab007}, - file = {:Gnecchi2021 - Precision Medicine and Cardiac Channelopathies_ When Dreams Meet Reality.pdf:PDF}, - groups = {Jan}, - shorttitle = {Precision {Medicine} and cardiac channelopathies}, - urldate = {2022-03-06}, -} - - - - -@Article{ERMENTROUT2002, - author = {G.Bard Ermentrout and Carson C. Chow}, - journal = {Physiology \& Behavior}, - title = {Modeling neural oscillations}, - year = {2002}, - issn = {0031-9384}, - number = {4}, - pages = {629-633}, - volume = {77}, - abstract = {A brief review of oscillatory activity in neurons and networks is given. Conditions required for neural oscillations are provided. Three mathematical methods for studying the coupling between neural oscillators are described: (i) weak coupling, (ii) firing time maps, and (iii) leaky integrate-and-fire methods. Several applications from macroscopic motor behavior to slice phenomena are provided.}, - doi = {10.1016/S0031-9384(02)00898-3}, - keywords = {Neural oscillators, Synchronization, Mathematical models}, -} - -@Article{verma_computational_2020, - author = {Verma, Parul and Kienle, Achim and Flockerzi, Dietrich and Ramkrishna, Doraiswami}, - journal = {Journal of Computational Neuroscience}, - title = {Computational analysis of a {9D} model for a small {DRG} neuron}, - year = {2020}, - issn = {1573-6873}, - month = nov, - number = {4}, - pages = {429--444}, - volume = {48}, - abstract = {Small dorsal root ganglion (DRG) neurons are primary nociceptors which are responsible for sensing pain. Elucidation of their dynamics is essential for understanding and controlling pain. To this end, we present a numerical bifurcation analysis of a small DRG neuron model in this paper. The model is of Hodgkin-Huxley type and has 9 state variables. It consists of a Nav1.7 and a Nav1.8 sodium channel, a leak channel, a delayed rectifier potassium, and an A-type transient potassium channel. The dynamics of this model strongly depend on the maximal conductances of the voltage-gated ion channels and the external current, which can be adjusted experimentally. We show that the neuron dynamics are most sensitive to the Nav1.8 channel maximal conductance (\${\textbackslash}overline \{g\}\_\{1.8\}\$). Numerical bifurcation analysis shows that depending on \${\textbackslash}overline \{g\}\_\{1.8\}\$and the external current, different parameter regions can be identified with stable steady states, periodic firing of action potentials, mixed-mode oscillations (MMOs), and bistability between stable steady states and stable periodic firing of action potentials. We illustrate and discuss the transitions between these different regimes. We further analyze the behavior of MMOs. As the external current is decreased, we find that MMOs appear after a cyclic limit point. Within this region, bifurcation analysis shows a sequence of isolated periodic solution branches with one large action potential and a number of small amplitude peaks per period. For decreasing external current, the number of small amplitude peaks is increasing and the distance between the large amplitude action potentials is growing, finally tending to infinity and thereby leading to a stable steady state. A closer inspection reveals more complex concatenated MMOs in between these periodic MMO branches, forming Farey sequences. Lastly, we also find small solution windows with aperiodic oscillations which seem to be chaotic. The dynamical patterns found here—as consequences of bifurcation points regulated by different parameters—have potential translational significance as repetitive firing of action potentials imply pain of some form and intensity; manipulating these patterns by regulating the different parameters could aid in investigating pain dynamics.}, - doi = {10.1007/s10827-020-00761-6}, - file = {Springer Full Text PDF:C\:/Users/nilsk/Zotero/storage/8VBIHVFQ/Verma et al. - 2020 - Computational analysis of a 9D model for a small D.pdf:application/pdf}, - language = {english}, - urldate = {2021-06-17}, -} - - - -@Article{Musto2020, - author = {Musto, Elisa and Gardella, Elena and Møller, Rikke S.}, - journal = {European Journal of Paediatric Neurology}, - title = {Recent advances in treatment of epilepsy-related sodium channelopathies}, - year = {2020}, - issn = {1090-3798}, - month = jan, - pages = {123--128}, - volume = {24}, - abstract = {Voltage-gated sodium channels (VGSCs) play a crucial role in generation of action potentials. Pathogenic variants in the five human brain expressed VGSC genes, SCN1A, SCN2A, SCN3A, SCN8A and SCN1B have been associated with a spectrum of epilepsy phenotypes and neurodevelopmental disorders. In the last decade, next generation sequencing techniques have revolutionized the way we diagnose these channelopathies, which is paving the way towards precision medicine. Knowing the functional effect (Loss-of-function versus Gain-of-function) of a variant is not only important for understanding the underlying pathophysiology, but it is particularly crucial to orient therapeutic decisions. Here we provide a review of the literature dealing with treatment options in epilepsy-related sodium channelopathies, including the current and emerging medications.}, - doi = {10.1016/j.ejpn.2019.12.009}, - groups = {Jan}, - keywords = {Epilepsy, SCN1A, SCN2A, SCN8A, SCN1B}, - language = {english}, - series = {Epilepsy \& {Neurodevelopmental} {Disorders}}, - urldate = {2022-03-03}, -} - -@Article{zhao_common_2020, - author = {Zhao, Juan and Petitjean, Dimitri and Haddad, Georges A. and Batulan, Zarah and Blunck, Rikard}, - journal = {International Journal of Molecular Sciences}, - title = {A {Common} {Kinetic} {Property} of {Mutations} {Linked} to {Episodic} {Ataxia} {Type} 1 {Studied} in the {Shaker} {Kv} {Channel}}, - year = {2020}, - month = jan, - number = {20}, - pages = {7602}, - volume = {21}, - abstract = {(1) Background: Episodic ataxia type 1 is caused by mutations in the KCNA1 gene encoding for the voltage-gated potassium channel Kv1.1. There have been many mutations in Kv1.1 linked to episodic ataxia reported and typically investigated by themselves or in small groups. The aim of this article is to determine whether we can define a functional parameter common to all Kv1.1 mutants that have been linked to episodic ataxia. (2) Methods: We introduced the disease mutations linked to episodic ataxia in the drosophila analog of Kv1.1, the Shaker Kv channel, and expressed the channels in Xenopus oocytes. Using the cut-open oocyte technique, we characterized the gating and ionic currents. (3) Results: We found that the episodic ataxia mutations variably altered the different gating mechanisms described for Kv channels. The common characteristic was a conductance voltage relationship and inactivation shifted to less polarized potentials. (4) Conclusions: We suggest that a combination of a prolonged action potential and slowed and incomplete inactivation leads to development of ataxia when Kv channels cannot follow or adapt to high firing rates.}, - copyright = {http://creativecommons.org/licenses/by/3.0/}, - doi = {10.3390/ijms21207602}, - file = {Full Text PDF:C\:/Users/nilsk/Zotero/storage/A2Q2B2UZ/Zhao et al. - 2020 - A Common Kinetic Property of Mutations Linked to E.pdf:application/pdf;Full Text PDF:C\:/Users/nilsk/Zotero/storage/7DVZLKI7/Zhao et al. - 2020 - A Common Kinetic Property of Mutations Linked to E.pdf:application/pdf;Snapshot:C\:/Users/nilsk/Zotero/storage/2EXHPJBW/7602.html:text/html;Snapshot:C\:/Users/nilsk/Zotero/storage/V8EV5IKK/7602.html:text/html}, - keywords = {electrophysiology, episodic ataxia, gating, voltage-gated potassium channel}, - language = {english}, - urldate = {2021-06-10}, -} - -@Article{manganas_identification_2001, - author = {Manganas, Louis N. and Wang, Qiang and Scannevin, Robert H. and Antonucci, Dana E. and Rhodes, Kenneth J. and Trimmer, James S.}, - journal = {Proceedings of the National Academy of Sciences}, - title = {Identification of a trafficking determinant localized to the {Kv1} potassium channel pore}, - year = {2001}, - issn = {0027-8424, 1091-6490}, - month = nov, - number = {24}, - pages = {14055--14059}, - volume = {98}, - abstract = {The repertoire of Kv1 potassium channels expressed in presynaptic terminals of mammalian central neurons is shaped by intrinsic trafficking signals that determine surface-expression efficiencies of homomeric and heteromeric Kv1 channel complexes. Here, we show that a determinant controlling surface expression of Kv1 channels is localized to the highly conserved pore region. Point-mutation analysis revealed two residues as critical for channel trafficking, one in the extracellular “turret” domain and one in the region distal to the selectivity filter. Interestingly, these same residues also form the binding sites for polypeptide neurotoxins. Our findings demonstrate a previously uncharacterized function for the channel-pore domain as a regulator of channel trafficking.}, - copyright = {Copyright © 2001, The National Academy of Sciences}, - doi = {10.1073/pnas.241403898}, - file = {Full Text PDF:C\:/Users/nilsk/Zotero/storage/USC4WDPI/Manganas et al. - 2001 - Identification of a trafficking determinant locali.pdf:application/pdf;Snapshot:C\:/Users/nilsk/Zotero/storage/9M7UBRBX/14055.html:text/html}, - language = {english}, - urldate = {2021-06-12}, -} - - -@Article{Saltelli2002, - author = {Saltelli, Andrea}, - journal = {Risk Analysis}, - title = {Sensitivity {Analysis} for {Importance} {Assessment}}, - year = {2002}, - issn = {1539-6924}, - number = {3}, - pages = {579--590}, - volume = {22}, - abstract = {We review briefly some examples that would support an extended role for quantitative sensitivity analysis in the context of model-based analysis (Section 1). We then review what features a quantitative sensitivity analysis needs to have to play such a role (Section 2). The methods that meet these requirements are described in Section 3; an example is provided in Section 4. Some pointers to further research are set out in Section 5.}, - doi = {10.1111/0272-4332.00040}, - file = {Full Text PDF:https\://onlinelibrary.wiley.com/doi/pdfdirect/10.1111/0272-4332.00040:application/pdf}, - keywords = {Uncertainty analysis, quantitative sensitivity analysis, computational models, assessment of importance, risk analysis}, - language = {english}, - urldate = {2022-04-12}, -} - - -@Article{yao2021taxonomy, - author = {Yao, Zizhen and others}, - journal = {Cell}, - title = {A taxonomy of transcriptomic cell types across the isocortex and hippocampal formation}, - year = {2021}, - number = {12}, - pages = {3222--3241}, - volume = {184}, - doi = {10.1101/2020.03.30.015214}, - publisher = {Elsevier}, -} - - -@Article{Cadwell2016, - author = {Cadwell, Cathryn R. and Palasantza, Athanasia and Jiang, Xiaolong and Berens, Philipp and Deng, Qiaolin and Yilmaz, Marlene and Reimer, Jacob and Shen, Shan and Bethge, Matthias and Tolias, Kimberley F. and Sandberg, Rickard and Tolias, Andreas S.}, - journal = {Nature Biotechnology}, - title = {Electrophysiological, transcriptomic and morphologic profiling of single neurons using {Patch}-seq}, - year = {2016}, - issn = {1546-1696}, - month = feb, - number = {2}, - pages = {199--203}, - volume = {34}, - abstract = {Patch-seq reveals new neuronal subtypes by combining electrophysiological and RNA-seq data on single neurons in situ.}, - copyright = {2015 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.}, - doi = {10.1038/nbt.3445}, - keywords = {Neuronal physiology, RNA sequencing}, - language = {english}, - publisher = {Nature Publishing Group}, -} - - -@Article{Scala2021, - author = {Scala, Federico and Kobak, Dmitry and Bernabucci, Matteo and Bernaerts, Yves and Cadwell, Cathryn René and Castro, Jesus Ramon and Hartmanis, Leonard and Jiang, Xiaolong and Laturnus, Sophie and Miranda, Elanine and Mulherkar, Shalaka and Tan, Zheng Huan and Yao, Zizhen and Zeng, Hongkui and Sandberg, Rickard and Berens, Philipp and Tolias, Andreas S.}, - journal = {Nature}, - title = {Phenotypic variation of transcriptomic cell types in mouse motor cortex}, - year = {2021}, - issn = {1476-4687}, - month = oct, - number = {7879}, - pages = {144--150}, - volume = {598}, - abstract = {Cortical neurons exhibit extreme diversity in gene expression as well as in morphological and electrophysiological properties1,2. Most existing neural taxonomies are based on either transcriptomic3,4 or morpho-electric5,6 criteria, as it has been technically challenging to study both aspects of neuronal diversity in the same set of cells7. Here we used Patch-seq8 to combine patch-clamp recording, biocytin staining, and single-cell RNA sequencing of more than 1,300 neurons in adult mouse primary motor cortex, providing a morpho-electric annotation of almost all transcriptomically defined neural cell types. We found that, although broad families of transcriptomic types (those expressing Vip, Pvalb, Sst and so on) had distinct and essentially non-overlapping morpho-electric phenotypes, individual transcriptomic types within the same family were not well separated in the morpho-electric space. Instead, there was a continuum of variability in morphology and electrophysiology, with neighbouring transcriptomic cell types showing similar morpho-electric features, often without clear boundaries between them. Our results suggest that neuronal types in the neocortex do not always form discrete entities. Instead, neurons form a hierarchy that consists of distinct non-overlapping branches at the level of families, but can form continuous and correlated transcriptomic and morpho-electrical landscapes within families.}, - copyright = {2020 The Author(s)}, - doi = {10.1038/s41586-020-2907-3}, - keywords = {Cellular neuroscience, Genetics of the nervous system}, - language = {english}, - publisher = {Nature Publishing Group}, -} - - -@Article{Xie2010, - author = {Xie, Gang and Harrison, John and Clapcote, Steven J. and Huang, Yun and Zhang, Jin-Yi and Wang, Lu-Yang and Roder, John C.}, - journal = {Journal of Biological Chemistry}, - title = {A {New} {Kv1}.2 {Channelopathy} {Underlying} {Cerebellar} {Ataxia} *}, - year = {2010}, - issn = {0021-9258, 1083-351X}, - month = oct, - number = {42}, - pages = {32160--32173}, - volume = {285}, - abstract = {{\textless}p{\textgreater}A forward genetic screen of mice treated with the mutagen ENU identified a mutant mouse with chronic motor incoordination. This mutant, named \textit{Pingu} (\textit{Pgu}), carries a missense mutation, an I402T substitution in the S6 segment of the voltage-gated potassium channel \textit{Kcna2.} The gene \textit{Kcna2} encodes the voltage-gated potassium channel α-subunit Kv1.2, which is abundantly expressed in the large axon terminals of basket cells that make powerful axo-somatic synapses onto Purkinje cells. Patch clamp recordings from cerebellar slices revealed an increased frequency and amplitude of spontaneous GABAergic inhibitory postsynaptic currents and reduced action potential firing frequency in Purkinje cells, suggesting that an increase in GABA release from basket cells is involved in the motor incoordination in \textit{Pgu} mice. In line with immunochemical analyses showing a significant reduction in the expression of Kv1 channels in the basket cell terminals of \textit{Pgu} mice, expression of homomeric and heteromeric channels containing the Kv1.2(I402T) α-subunit in cultured CHO cells revealed subtle changes in biophysical properties but a dramatic decrease in the amount of functional Kv1 channels. Pharmacological treatment with acetazolamide or transgenic complementation with wild-type \textit{Kcna2} cDNA partially rescued the motor incoordination in \textit{Pgu} mice. These results suggest that independent of known mutations in \textit{Kcna1} encoding Kv1.1, \textit{Kcna2} mutations may be important molecular correlates underlying human cerebellar ataxic disease.{\textless}/p{\textgreater}}, - doi = {10.1074/jbc.M110.153676}, - language = {English}, - publisher = {Elsevier}, - urldate = {2022-05-06}, -} - - -@Article{Mantegazza2019, - author = {Mantegazza, Massimo and Broccoli, Vania}, - journal = {Epilepsia}, - title = {{SCN1A}/{NaV1}.1 channelopathies: {Mechanisms} in expression systems, animal models, and human {iPSC} models}, - year = {2019}, - issn = {1528-1167}, - number = {S3}, - pages = {S25--S38}, - volume = {60}, - abstract = {Pathogenic SCN1A/NaV1.1 mutations cause well-defined epilepsies, including genetic epilepsy with febrile seizures plus (GEFS+) and the severe epileptic encephalopathy Dravet syndrome. In addition, they cause a severe form of migraine with aura, familial hemiplegic migraine. Moreover, SCN1A/NaV1.1 variants have been inferred as risk factors in other types of epilepsy. We review here the advancements obtained studying pathologic mechanisms of SCN1A/NaV1.1 mutations with experimental systems. We present results gained with in vitro expression systems, gene-targeted animal models, and the induced pluripotent stem cell (iPSC) technology, highlighting advantages, limits, and pitfalls for each of these systems. Overall, the results obtained in the last two decades confirm that the initial pathologic mechanism of epileptogenic SCN1A/NaV1.1 mutations is loss-of-function of NaV1.1 leading to hypoexcitability of at least some types of γ-aminobutyric acid (GABA)ergic neurons (including cortical and hippocampal parvalbumin-positive and somatostatin-positive ones). Conversely, more limited results point to NaV1.1 gain-of-function for familial hemiplegic migraine (FHM) mutations. Behind these relatively simple pathologic mechanisms, an unexpected complexity has been observed, in part generated by technical issues in experimental studies and in part related to intrinsically complex pathophysiologic responses and remodeling, which yet remain to be fully disentangled.}, - doi = {10.1111/epi.14700}, - file = {Full Text PDF:https\://onlinelibrary.wiley.com/doi/pdfdirect/10.1111/epi.14700:application/pdf}, - keywords = {Dravet syndrome, epilepsy, FHM, GABA, genetic epilepsy with febrile seizures plus, migraine, remodeling, seizures}, - language = {english}, - shorttitle = {{SCN1A}/{NaV1}.1 channelopathies}, - urldate = {2022-05-06}, -} - - -@InCollection{Habib2015, - author = {Habib, Abdella M. and Wood, John N. and Cox, James J.}, - publisher = {Springer}, - title = {Sodium {Channels} and {Pain}}, - year = {2015}, - address = {Berlin, Heidelberg}, - editor = {Schaible, Hans-Georg}, - isbn = {9783662464502}, - pages = {39--56}, - series = {Handbook of {Experimental} {Pharmacology}}, - abstract = {Human and mouse genetic studies have led to significant advances in our understanding of the role of voltage-gated sodium channels in pain pathways. In this chapter, we focus on Nav1.7, Nav1.8, Nav1.9 and Nav1.3 and describe the insights gained from the detailed analyses of global and conditional transgenic Nav knockout mice in terms of pain behaviour. The spectrum of human disorders caused by mutations in these channels is also outlined, concluding with a summary of recent progress in the development of selective Nav1.7 inhibitors for the treatment of pain.}, - file = {:Habib2015 - Sodium Channels and Pain.html:URL}, - keywords = {Voltage-gated sodium channels, Channelopathy, Transgenic mice, Analgesia, Chronic pain, Sensory neurons}, - language = {english}, - urldate = {2022-05-06}, -} - - -@Article{Lory2020, - author = {Lory, Philippe and Nicole, Sophie and Monteil, Arnaud}, - journal = {Pflügers Archiv - European Journal of Physiology}, - title = {Neuronal {Cav3} channelopathies: recent progress and perspectives}, - year = {2020}, - issn = {1432-2013}, - month = jul, - number = {7}, - pages = {831--844}, - volume = {472}, - abstract = {T-type, low-voltage activated, calcium channels, now designated Cav3 channels, are involved in a wide variety of physiological functions, especially in nervous systems. Their unique electrophysiological properties allow them to finely regulate neuronal excitability and to contribute to sensory processing, sleep, and hormone and neurotransmitter release. In the last two decades, genetic studies, including exploration of knock-out mouse models, have greatly contributed to elucidate the role of Cav3 channels in normal physiology, their regulation, and their implication in diseases. Mutations in genes encoding Cav3 channels (CACNA1G, CACNA1H, and CACNA1I) have been linked to a variety of neurodevelopmental, neurological, and psychiatric diseases designated here as neuronal Cav3 channelopathies. In this review, we describe and discuss the clinical findings and supporting in vitro and in vivo studies of the mutant channels, with a focus on de novo, gain-of-function missense mutations recently discovered in CACNA1G and CACNA1H. Overall, the studies of the Cav3 channelopathies help deciphering the pathogenic mechanisms of corresponding diseases and better delineate the properties and physiological roles Cav3 channels.}, - doi = {10.1007/s00424-020-02429-7}, - file = {:Lory2020 - Neuronal Cav3 Channelopathies_ Recent Progress and Perspectives.pdf:PDF}, - keywords = {Calcium channels, T-type, Calcium channelopathies, Epilepsy, Ataxia, Autism, Schizophrenia, Primary aldosteronism}, - language = {english}, - shorttitle = {Neuronal {Cav3} channelopathies}, - urldate = {2022-05-06}, -} - - -@Article{Hedrich2019, - author = {Hedrich, Ulrike B. S. and Lauxmann, Stephan and Lerche, Holger}, - journal = {Epilepsia}, - title = {{SCN2A} channelopathies: {Mechanisms} and models}, - year = {2019}, - issn = {1528-1167}, - number = {S3}, - pages = {S68--S76}, - volume = {60}, - abstract = {Variants in the SCN2A gene, encoding the voltage-gated sodium channel NaV1.2, cause a variety of neuropsychiatric syndromes with different severity ranging from self-limiting epilepsies with early onset to developmental and epileptic encephalopathy with early or late onset and intellectual disability (ID), as well as ID or autism without seizures. Functional analysis of channel defects demonstrated a genotype-phenotype correlation and suggested effective treatment options for one group of affected patients carrying gain-of-function variants. Here, we sum up the functional mechanisms underlying different phenotypes of patients with SCN2A channelopathies and present currently available models that can help in understanding SCN2A-related disorders.}, - doi = {10.1111/epi.14731}, - file = {Full Text PDF:https\://onlinelibrary.wiley.com/doi/pdfdirect/10.1111/epi.14731:application/pdf}, - keywords = {developmental and epileptic encephalopathy, genotype-phenotype correlation, NaV1.2 channel defect, pathomechanisms, SCN2A channelopathies}, - language = {english}, - shorttitle = {{SCN2A} channelopathies}, - urldate = {2022-05-06}, -} - - -@Article{Orsini2018, - author = {Orsini, Alessandro and Esposito, Mariagrazia and Perna, Daniele and Bonuccelli, Alice and Peroni, Diego and Striano, Pasquale}, - journal = {Journal of Translational Genetics and Genomics}, - title = {Personalized medicine in epilepsy patients}, - year = {2018}, - month = oct, - pages = {16}, - volume = {2}, - abstract = {Personalized medicine in epilepsy patients}, - doi = {10.20517/jtgg.2018.14}, - file = {:Orsini2018 - Personalized Medicine in Epilepsy Patients.pdf:PDF}, - language = {english}, - publisher = {OAE Publishing Inc.}, - urldate = {2022-05-06}, -} - - -@Article{Yang2018, - author = {Yang, Yang and Mis, Malgorzata A. and Estacion, Mark and Dib-Hajj, Sulayman D. and Waxman, Stephen G.}, - journal = {Trends in Pharmacological Sciences}, - title = {{NaV1}.7 as a {Pharmacogenomic} {Target} for {Pain}: {Moving} {Toward} {Precision} {Medicine}}, - year = {2018}, - issn = {0165-6147}, - month = mar, - number = {3}, - pages = {258--275}, - volume = {39}, - abstract = {Chronic pain is a global unmet medical need. Most existing treatments are only partially effective or have side effects that limit their use. Rapid progress in elucidating the contribution of specific genes, including those that encode peripheral voltage-gated sodium channels, to the pathobiology of chronic pain suggests that it may be possible to advance pain pharmacotherapy. Focusing on voltage-gated sodium channel NaV1.7 as an example, this article reviews recent progress in developing patient-specific induced pluripotent stem cells (iPSCs) and their differentiation into sensory neurons, together with advances in structural modeling, that have provided a basis for first-in-human translational studies. These new approaches will hopefully transform the treatment of pain from trial-and-error toward genomically guided, precision pharmacotherapy.}, - doi = {10.1016/j.tips.2017.11.010}, - language = {english}, - shorttitle = {{NaV1}.7 as a {Pharmacogenomic} {Target} for {Pain}}, - urldate = {2022-05-06}, -} - - -@Article{Kullmann2002, - author = {Kullmann, Dimitri M.}, - journal = {Brain}, - title = {The neuronal channelopathies}, - year = {2002}, - issn = {0006-8950}, - month = jun, - number = {6}, - pages = {1177--1195}, - volume = {125}, - abstract = {This review addresses the molecular and cellular mechanisms of diseases caused by inherited mutations of ion channels in neurones. Among important recent advances is the elucidation of several dominantly inherited epilepsies caused by mutations of both voltage‐gated and ligand‐gated ion channels. The neuronal channelopathies show evidence of phenotypic convergence; notably, episodic ataxia can be caused by mutations of either calcium or potassium channels. The channelopathies also show evidence of phenotypic divergence; for instance, different mutations of the same calcium channel gene are associated with familial hemiplegic migraine, episodic or progressive ataxia, coma and epilepsy. Future developments are likely to include the discovery of other ion channel genes associated with inherited and sporadic CNS disorders. The full range of manifestations of inherited ion channel mutations remains to be established.}, - doi = {10.1093/brain/awf130}, - file = {:Kullmann2002 - The Neuronal Channelopathies.pdf:PDF}, - urldate = {2022-05-06}, -} - - - - -@Article{Waxman2011, - author = {Waxman, Stephen G.}, - journal = {Nature}, - title = {Channelopathies have many faces}, - year = {2011}, - issn = {1476-4687}, - month = apr, - number = {7342}, - pages = {173--174}, - volume = {472}, - abstract = {A sodium channel known for its role in the perception of pain also seems to be necessary for olfaction. The multiple roles of this channel and the diverse effects of its mutations raise intriguing questions. See Article p.186}, - copyright = {2011 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.}, - doi = {10.1038/472173a}, - keywords = {Animal behaviour, Channelopathies, Physiology}, - language = {english}, - publisher = {Nature Publishing Group}, - urldate = {2022-05-06}, -} - - -@Article{Niday2018, - author = {Niday, Zachary and Tzingounis, Anastasios V.}, - journal = {The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry}, - title = {Potassium channel gain of function in epilepsy: an unresolved paradox}, - year = {2018}, - issn = {1073-8584}, - month = aug, - number = {4}, - pages = {368--380}, - volume = {24}, - abstract = {Exome and targeted sequencing have revolutionized clinical diagnosis. This has been particularly striking in epilepsy and neurodevelopmental disorders, for which new genes or new variants of pre-existing candidate genes are being continuously identified at increasing rates every year. A surprising finding of these efforts is the recognition that gain of function potassium channel variants are actually associated with certain types of epilepsy, such as malignant migrating partial seizures of infancy or early-onset epileptic encephalopathy. This development has been difficult to understand as traditionally potassium channel loss-of-function, not gain-of-function, has been associated with hyperexcitability disorders. Here, we describe the current state of the field regarding the gain-of-function potassium channel variants associated with epilepsy (KCNA2, KCNB1, KCND2, KCNH1, KCNH5, KCNJ10, KCNMA1, KCNQ2, KCNQ3, and KCNT1) and speculate on the possible cellular mechanisms behind the development of seizures and epilepsy in these patients. Understanding how potassium channel gain-of-function leads to epilepsy will provide new insights into the inner working of neural circuits and aid in developing new therapies.}, - doi = {10.1177/1073858418763752}, - pmcid = {PMC6045440}, - pmid = {29542386}, - shorttitle = {Potassium channel gain of function in epilepsy}, -} - - -@Article{Huang2019, - author = {Huang, Z. Josh and Paul, Anirban}, - journal = {Nature Reviews Neuroscience}, - title = {The diversity of {GABAergic} neurons and neural communication elements}, - year = {2019}, - issn = {1471-0048}, - month = sep, - number = {9}, - pages = {563--572}, - volume = {20}, - abstract = {The phenotypic diversity of cortical GABAergic neurons is probably necessary for their functional versatility in shaping the spatiotemporal dynamics of neural circuit operations underlying cognition. Deciphering the logic of this diversity requires comprehensive analysis of multi-modal cell features and a framework of neuronal identity that reflects biological mechanisms and principles. Recent high-throughput single-cell analyses have generated unprecedented data sets characterizing the transcriptomes, morphology and electrophysiology of interneurons. We posit that cardinal interneuron types can be defined by their synaptic communication properties, which are encoded in key transcriptional signatures. This conceptual framework integrates multi-modal cell features, captures neuronal input–output properties fundamental to circuit operation and may advance understanding of the appropriate granularity of neuron types, towards a biologically grounded and operationally useful interneuron taxonomy.}, - copyright = {2019 The Publisher}, - doi = {10.1038/s41583-019-0195-4}, - file = {Full Text PDF:https\://www.nature.com/articles/s41583-019-0195-4.pdf:application/pdf}, - keywords = {Cellular neuroscience, Molecular neuroscience, Neural circuits}, - language = {english}, - publisher = {Nature Publishing Group}, - -} - - -@Article{Gouwens2019, - author = {Gouwens, Nathan W. and others}, - journal = {Nature Neuroscience}, - title = {Classification of electrophysiological and morphological neuron types in the mouse visual cortex}, - year = {2019}, - issn = {1546-1726}, - month = jul, - number = {7}, - pages = {1182--1195}, - volume = {22}, - abstract = {Understanding the diversity of cell types in the brain has been an enduring challenge and requires detailed characterization of individual neurons in multiple dimensions. To systematically profile morpho-electric properties of mammalian neurons, we established a single-cell characterization pipeline using standardized patch-clamp recordings in brain slices and biocytin-based neuronal reconstructions. We built a publicly accessible online database, the Allen Cell Types Database, to display these datasets. Intrinsic physiological properties were measured from 1,938 neurons from the adult laboratory mouse visual cortex, morphological properties were measured from 461 reconstructed neurons, and 452 neurons had both measurements available. Quantitative features were used to classify neurons into distinct types using unsupervised methods. We established a taxonomy of morphologically and electrophysiologically defined cell types for this region of the cortex, with 17 electrophysiological types, 38 morphological types and 46 morpho-electric types. There was good correspondence with previously defined transcriptomic cell types and subclasses using the same transgenic mouse lines.}, - copyright = {2019 The Author(s), under exclusive licence to Springer Nature America, Inc.}, - doi = {10.1038/s41593-019-0417-0}, - keywords = {Cellular neuroscience, Striate cortex}, - language = {english}, - publisher = {Nature Publishing Group}, -} - - -@Article{Kozareva2021, - author = {Kozareva, Velina and Martin, Caroline and Osorno, Tomas and Rudolph, Stephanie and Guo, Chong and Vanderburg, Charles and Nadaf, Naeem and Regev, Aviv and Regehr, Wade G. and Macosko, Evan}, - journal = {Nature}, - title = {A transcriptomic atlas of mouse cerebellar cortex comprehensively defines cell types}, - year = {2021}, - issn = {1476-4687}, - month = oct, - number = {7879}, - pages = {214--219}, - volume = {598}, - abstract = {The cerebellar cortex is a well-studied brain structure with diverse roles in motor learning, coordination, cognition and autonomic regulation. However, a complete inventory of cerebellar cell types is currently lacking. Here, using recent advances in high-throughput transcriptional profiling1–3, we molecularly define cell types across individual lobules of the adult mouse cerebellum. Purkinje neurons showed considerable regional specialization, with the greatest diversity occurring in the posterior lobules. For several types of cerebellar interneuron, the molecular variation within each type was more continuous, rather than discrete. In particular, for the unipolar brush cells—an interneuron population previously subdivided into discrete populations—the continuous variation in gene expression was associated with a graded continuum of electrophysiological properties. Notably, we found that molecular layer interneurons were composed of two molecularly and functionally distinct types. Both types show a continuum of morphological variation through the thickness of the molecular layer, but electrophysiological recordings revealed marked differences between the two types in spontaneous firing, excitability and electrical coupling. Together, these findings provide a comprehensive cellular atlas of the cerebellar cortex, and outline a methodological and conceptual framework for the integration of molecular, morphological and physiological ontologies for defining brain cell types.}, - copyright = {2021 The Author(s)}, - doi = {10.1038/s41586-021-03220-z}, - file = {Full Text PDF:https\://www.nature.com/articles/s41586-021-03220-z.pdf:application/pdf}, - keywords = {Cellular neuroscience, Genomics}, - language = {english}, - publisher = {Nature Publishing Group}, -} - - -@Article{Baden2016, - author = {Baden, Tom and Berens, Philipp and Franke, Katrin and Rosón, Miroslav Román and Bethge, Matthias and Euler, Thomas}, - journal = {Nature}, - title = {The functional diversity of retinal ganglion cells in the mouse}, - year = {2016}, - issn = {0028-0836}, - month = jan, - number = {7586}, - pages = {345--350}, - volume = {529}, - abstract = {In the vertebrate visual system, all output of the retina is carried by retinal ganglion cells. Each type encodes distinct visual features in parallel for transmission to the brain. How many such “output channels” exist and what each encodes is an area of intense debate. In mouse, anatomical estimates range between 15–20 channels, and only a handful are functionally understood. Combining two-photon calcium imaging to obtain dense retinal recordings and unsupervised clustering of the resulting sample of {\textgreater}11,000 cells, we here show that the mouse retina harbours substantially more than 30 functional output channels. These include all known and several new ganglion cell types, as verified by genetic and anatomical criteria. Therefore, information channels from the mouse’s eye to the mouse’s brain are considerably more diverse than shown thus far by anatomical studies, suggesting an encoding strategy resembling that used in state-of-the-art artificial vision systems.}, - doi = {10.1038/nature16468}, - file = {PubMed Central Link:https\://www.ncbi.nlm.nih.gov/pmc/articles/PMC4724341/:text/html}, - pmcid = {PMC4724341}, - pmid = {26735013}, -} - - -@Article{Poulin2016, - author = {Poulin, Jean-Francois and Tasic, Bosiljka and Hjerling-Leffler, Jens and Trimarchi, Jeffrey M. and Awatramani, Rajeshwar}, - journal = {Nature Neuroscience}, - title = {Disentangling neural cell diversity using single-cell transcriptomics}, - year = {2016}, - issn = {1546-1726}, - month = sep, - number = {9}, - pages = {1131--1141}, - volume = {19}, - abstract = {Although single-cell gene expression profiling has been possible for the past two decades, a number of recent technological advances in microfluidic and sequencing technology have recently made the procedure much easier and less expensive. Awatramani and colleagues discuss the use of single-cell gene expression profiling for classifying neuronal cell types.}, - copyright = {2016 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.}, - doi = {10.1038/nn.4366}, - file = {Full Text PDF:https\://www.nature.com/articles/nn.4366.pdf:application/pdf}, - keywords = {Cellular neuroscience, Molecular neuroscience, Transcriptomics}, - language = {english}, - publisher = {Nature Publishing Group}, -} - - -@Article{Alkaslasi2021, - author = {Alkaslasi, Mor R. and Piccus, Zoe E. and Hareendran, Sangeetha and Silberberg, Hanna and Chen, Li and Zhang, Yajun and Petros, Timothy J. and Le Pichon, Claire E.}, - journal = {Nature Communications}, - title = {Single nucleus {RNA}-sequencing defines unexpected diversity of cholinergic neuron types in the adult mouse spinal cord}, - year = {2021}, - issn = {2041-1723}, - month = apr, - number = {1}, - pages = {2471}, - volume = {12}, - abstract = {In vertebrates, motor control relies on cholinergic neurons in the spinal cord that have been extensively studied over the past hundred years, yet the full heterogeneity of these neurons and their different functional roles in the adult remain to be defined. Here, we develop a targeted single nuclear RNA sequencing approach and use it to identify an array of cholinergic interneurons, visceral and skeletal motor neurons. Our data expose markers for distinguishing these classes of cholinergic neurons and their rich diversity. Specifically, visceral motor neurons, which provide autonomic control, can be divided into more than a dozen transcriptomic classes with anatomically restricted localization along the spinal cord. The complexity of the skeletal motor neurons is also reflected in our analysis with alpha, gamma, and a third subtype, possibly corresponding to the elusive beta motor neurons, clearly distinguished. In combination, our data provide a comprehensive transcriptomic description of this important population of neurons that control many aspects of physiology and movement and encompass the cellular substrates for debilitating degenerative disorders.}, - copyright = {2021 This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply}, - doi = {10.1038/s41467-021-22691-2}, - file = {Full Text PDF:https\://www.nature.com/articles/s41467-021-22691-2.pdf:application/pdf}, - keywords = {Cellular neuroscience, Molecular neuroscience, Motor neuron, Spinal cord, Transcriptomics}, - language = {english}, - publisher = {Nature Publishing Group}, -} - - -@Article{Voigt2019, - author = {Voigt, A. P. and Whitmore, S. S. and Flamme-Wiese, M. J. and Riker, M. J. and Wiley, L. A. and Tucker, B. A. and Stone, E. M. and Mullins, R. F. and Scheetz, T. E.}, - journal = {Experimental Eye Research}, - title = {Molecular characterization of foveal versus peripheral human retina by single-cell {RNA} sequencing}, - year = {2019}, - issn = {0014-4835}, - month = jul, - pages = {234--242}, - volume = {184}, - abstract = {The human retina is a complex tissue responsible for detecting photons of light and converting information from these photons into the neurochemical signals interpreted as vision. Such visual signaling not only requires sophisticated interactions between multiple classes of neurons, but also spatially-dependent molecular specialization of individual cell types. In this study, we performed single-cell RNA sequencing on neural retina isolated from both the fovea and peripheral retina in three human donors. We recovered a total of 8,217 cells, with 3,578 cells originating from the fovea and 4,639 cells originating from the periphery. Expression profiles for all major retinal cell types were compiled, and differential expression analysis was performed between cells of foveal versus peripheral origin. Globally, mRNA for the serum iron binding protein transferrin (TF), which has been associated with age-related macular degeneration pathogenesis, was enriched in peripheral samples. Cone photoreceptor cells were of particular interest and formed two predominant clusters based on gene expression. One cone cluster had 96\% of cells originating from foveal samples, while the second cone cluster consisted exclusively of peripherally isolated cells. A total of 148 genes were differentially expressed between cones from the fovea versus periphery. Interestingly, peripheral cones were enriched for the gene encoding Beta-Carotene Oxygenase 2 (BCO2). A relative deficiency of this enzyme may account for the accumulation of carotenoids responsible for yellow pigment deposition within the macula. Overall, this data set provides rich expression profiles of the major human retinal cell types and highlights transcriptomic features that distinguish foveal and peripheral cells.}, - doi = {10.1016/j.exer.2019.05.001}, - file = {ScienceDirect Full Text PDF:https\://www.sciencedirect.com/science/article/pii/S0014483519302726/pdfft?md5=099a053a74940e3ca26986bb68c2e4ec&pid=1-s2.0-S0014483519302726-main.pdf&isDTMRedir=Y:application/pdf}, - keywords = {Retina, Cones, Fovea, Single-cell, Transferrin}, - language = {english}, -} - - -@Article{Berens2017, - author = {Berens, Philipp and Euler, Thomas}, - journal = {e-Neuroforum}, - title = {Neuronal {Diversity} {In} {The} {Retina}}, - year = {2017}, - issn = {1868-856X}, - month = may, - number = {2}, - pages = {93--101}, - volume = {23}, - abstract = {The retina in the eye performs complex computations, to transmit only behaviourally relevant information about our visual environment to the brain. These computations are implemented by numerous different cell types that form complex circuits. New experimental and computational methods make it possible to study the cellular diversity of the retina in detail – the goal of obtaining a complete list of all the cell types in the retina and, thus, its “building blocks”, is within reach. We review the current state of this endeavour and highlight possible directions for future research.}, - chapter = {Neuroforum}, - doi = {10.1515/nf-2016-A055}, - keywords = {Retina, Eye, Cell Types, Networks, Neural circuits}, - language = {english}, - publisher = {De Gruyter}, -} - - -@Article{Cadwell2020, - author = {Cadwell, Cathryn R and Scala, Federico and Fahey, Paul G and Kobak, Dmitry and Mulherkar, Shalaka and Sinz, Fabian H and Papadopoulos, Stelios and Tan, Zheng H and Johnsson, Per and Hartmanis, Leonard and Li, Shuang and Cotton, Ronald J and Tolias, Kimberley F and Sandberg, Rickard and Berens, Philipp and Jiang, Xiaolong and Tolias, Andreas Savas}, - journal = {eLife}, - title = {Cell type composition and circuit organization of clonally related excitatory neurons in the juvenile mouse neocortex}, - year = {2020}, - issn = {2050-084X}, - month = mar, - pages = {e52951}, - volume = {9}, - abstract = {Clones of excitatory neurons derived from a common progenitor have been proposed to serve as elementary information processing modules in the neocortex. To characterize the cell types and circuit diagram of clonally related excitatory neurons, we performed multi-cell patch clamp recordings and Patch-seq on neurons derived from Nestin-positive progenitors labeled by tamoxifen induction at embryonic day 10.5. The resulting clones are derived from two radial glia on average, span cortical layers 2–6, and are composed of a random sampling of transcriptomic cell types. We find an interaction between shared lineage and connection type: related neurons are more likely to be connected vertically across cortical layers, but not laterally within the same layer. These findings challenge the view that related neurons show uniformly increased connectivity and suggest that integration of vertical intra-clonal input with lateral inter-clonal input may represent a developmentally programmed connectivity motif supporting the emergence of functional circuits.}, - doi = {10.7554/eLife.52951}, - editor = {West, Anne E and Behrens, Timothy E and Hevner, Robert and Fishell, Gordon}, - file = {:Cadwell2020 - Cell Type Composition and Circuit Organization of Clonally Related Excitatory Neurons in the Juvenile Mouse Neocortex.pdf:PDF}, - keywords = {cell lineage, connectivity, clonally related, excitatory neurons, cortical development, transcriptomics}, - publisher = {eLife Sciences Publications, Ltd}, -} - - -@Article{Laturnus2020, - author = {Laturnus, Sophie and Kobak, Dmitry and Berens, Philipp}, - journal = {Neuroinformatics}, - title = {A {Systematic} {Evaluation} of {Interneuron} {Morphology} {Representations} for {Cell} {Type} {Discrimination}}, - year = {2020}, - issn = {1559-0089}, - month = oct, - number = {4}, - pages = {591--609}, - volume = {18}, - abstract = {Quantitative analysis of neuronal morphologies usually begins with choosing a particular feature representation in order to make individual morphologies amenable to standard statistics tools and machine learning algorithms. Many different feature representations have been suggested in the literature, ranging from density maps to intersection profiles, but they have never been compared side by side. Here we performed a systematic comparison of various representations, measuring how well they were able to capture the difference between known morphological cell types. For our benchmarking effort, we used several curated data sets consisting of mouse retinal bipolar cells and cortical inhibitory neurons. We found that the best performing feature representations were two-dimensional density maps, two-dimensional persistence images and morphometric statistics, which continued to perform well even when neurons were only partially traced. Combining these feature representations together led to further performance increases suggesting that they captured non-redundant information. The same representations performed well in an unsupervised setting, implying that they can be suitable for dimensionality reduction or clustering.}, - doi = {10.1007/s12021-020-09461-z}, - file = {:Laturnus2020 - A Systematic Evaluation of Interneuron Morphology Representations for Cell Type Discrimination.pdf:PDF}, - keywords = {Neuroanatomy, Benchmarking, Cell types, Mouse, Visual cortex}, - language = {english}, -} - - -@Article{Yan2020b, - author = {Yan, Wenjun and Peng, Yi-Rong and van Zyl, Tavé and Regev, Aviv and Shekhar, Karthik and Juric, Dejan and Sanes, Joshua R.}, - journal = {Scientific Reports}, - title = {Cell {Atlas} of {The} {Human} {Fovea} and {Peripheral} {Retina}}, - year = {2020b}, - issn = {2045-2322}, - month = jun, - number = {1}, - pages = {9802}, - volume = {10}, - abstract = {Most irreversible blindness results from retinal disease. To advance our understanding of the etiology of blinding diseases, we used single-cell RNA-sequencing (scRNA-seq) to analyze the transcriptomes of {\textasciitilde}85,000 cells from the fovea and peripheral retina of seven adult human donors. Utilizing computational methods, we identified 58 cell types within 6 classes: photoreceptor, horizontal, bipolar, amacrine, retinal ganglion and non-neuronal cells. Nearly all types are shared between the two retinal regions, but there are notable differences in gene expression and proportions between foveal and peripheral cohorts of shared types. We then used the human retinal atlas to map expression of 636 genes implicated as causes of or risk factors for blinding diseases. Many are expressed in striking cell class-, type-, or region-specific patterns. Finally, we compared gene expression signatures of cell types between human and the cynomolgus macaque monkey, Macaca fascicularis. We show that over 90\% of human types correspond transcriptomically to those previously identified in macaque, and that expression of disease-related genes is largely conserved between the two species. These results validate the use of the macaque for modeling blinding disease, and provide a foundation for investigating molecular mechanisms underlying visual processing.}, - copyright = {2020 The Author(s)}, - doi = {10.1038/s41598-020-66092-9}, - keywords = {Diseases of the nervous system, Eye diseases, Neuroscience, Sensory systems}, - language = {english}, - publisher = {Nature Publishing Group}, -} - - -@Article{Yan2020a, - author = {Yan, Wenjun and Laboulaye, Mallory A. and Tran, Nicholas M. and Whitney, Irene E. and Benhar, Inbal and Sanes, Joshua R.}, - journal = {Journal of Neuroscience}, - title = {Mouse {Retinal} {Cell} {Atlas}: {Molecular} {Identification} of over {Sixty} {Amacrine} {Cell} {Types}}, - year = {2020a}, - issn = {0270-6474, 1529-2401}, - month = jul, - number = {27}, - pages = {5177--5195}, - volume = {40}, - chapter = {Research Articles}, - doi = {10.1523/JNEUROSCI.0471-20.2020}, - language = {english}, - pmid = {32457074}, - publisher = {Society for Neuroscience}, -} - - -@Article{Gouwens2018, - author = {Gouwens, Nathan W. and Berg, Jim and Feng, David and Sorensen, Staci A. and Zeng, Hongkui and Hawrylycz, Michael J. and Koch, Christof and Arkhipov, Anton}, - journal = {Nature Communications}, - title = {Systematic generation of biophysically detailed models for diverse cortical neuron types}, - year = {2018}, - issn = {2041-1723}, - month = feb, - number = {1}, - pages = {710}, - volume = {9}, - abstract = {The cellular components of mammalian neocortical circuits are diverse, and capturing this diversity in computational models is challenging. Here we report an approach for generating biophysically detailed models of 170 individual neurons in the Allen Cell Types Database to link the systematic experimental characterization of cell types to the construction of cortical models. We build models from 3D morphologies and somatic electrophysiological responses measured in the same cells. Densities of active somatic conductances and additional parameters are optimized with a genetic algorithm to match electrophysiological features. We evaluate the models by applying additional stimuli and comparing model responses to experimental data. Applying this technique across a diverse set of neurons from adult mouse primary visual cortex, we verify that models preserve the distinctiveness of intrinsic properties between subsets of cells observed in experiments. The optimized models are accessible online alongside the experimental data. Code for optimization and simulation is also openly distributed.}, - copyright = {2018 The Author(s)}, - doi = {10.1038/s41467-017-02718-3}, - file = {Full Text PDF:https\://www.nature.com/articles/s41467-017-02718-3.pdf:application/pdf}, - keywords = {Biophysical models, Cellular neuroscience, Striate cortex}, - language = {english}, - publisher = {Nature Publishing Group}, - ranking = {rank4}, -} - - -@Article{Tripathy2015, - author = {Tripathy, Shreejoy J. and Burton, Shawn D. and Geramita, Matthew and Gerkin, Richard C. and Urban, Nathaniel N.}, - journal = {Journal of Neurophysiology}, - title = {Brain-wide analysis of electrophysiological diversity yields novel categorization of mammalian neuron types}, - year = {2015}, - issn = {0022-3077}, - month = jun, - number = {10}, - pages = {3474--3489}, - volume = {113}, - abstract = {For decades, neurophysiologists have characterized the biophysical properties of a rich diversity of neuron types. However, identifying common features and computational roles shared across neuron types is made more difficult by inconsistent conventions for collecting and reporting biophysical data. Here, we leverage NeuroElectro, a literature-based database of electrophysiological properties (www.neuroelectro.org), to better understand neuronal diversity, both within and across neuron types, and the confounding influences of methodological variability. We show that experimental conditions (e.g., electrode types, recording temperatures, or animal age) can explain a substantial degree of the literature-reported biophysical variability observed within a neuron type. Critically, accounting for experimental metadata enables massive cross-study data normalization and reveals that electrophysiological data are far more reproducible across laboratories than previously appreciated. Using this normalized dataset, we find that neuron types throughout the brain cluster by biophysical properties into six to nine superclasses. These classes include intuitive clusters, such as fast-spiking basket cells, as well as previously unrecognized clusters, including a novel class of cortical and olfactory bulb interneurons that exhibit persistent activity at theta-band frequencies.}, - doi = {10.1152/jn.00237.2015}, - file = {:Tripathy2015 - Brain Wide Analysis of Electrophysiological Diversity Yields Novel Categorization of Mammalian Neuron Types.pdf:PDF}, - keywords = {neuron biophysics, intrinsic membrane properties, electrophysiology, neuron diversity, neuroinformatics, text mining, databases}, - publisher = {American Physiological Society}, - -} - - -@Article{Gu2014, - author = {Gu, HuaGuang and Chen, ShengGen}, - journal = {Science China Technological Sciences}, - title = {Potassium-induced bifurcations and chaos of firing patterns observed from biological experiment on a neural pacemaker}, - year = {2014}, - issn = {1869-1900}, - month = may, - number = {5}, - pages = {864--871}, - volume = {57}, - abstract = {Changes of neural firing patterns and transitions between firing patterns induced by the introduction of external stimulation or adjustment of biological parameter have been demonstrated to play key roles in information coding. In this paper, bifurcation processes of bursting patterns were observed from an experimental neural pacemaker, through the adjustment of potassium parameter including ion concentration and calcium-dependent channel conductance. The adjustment of calcium-dependent potassium channel conductance was achieved by changing the extracellular tetraethylammonium concentration. The deterministic dynamics of chaotic bursting patterns induced by period-doubling bifurcation and intermittency, and lying between two periodic bursting patterns in a period-adding bifurcation process was investigated with a nonlinear prediction method. The bifurcations included period-doubling and period-adding bifurcations of bursting patterns. The experimental bifurcations and chaos closely matched those previously simulated in the theoretical neuronal model by adjusting potassium parameter, which demonstrated the simulation results of the theoretical model. The experimental results indicate that the potassium concentration and conductance of calcium-dependent potassium channel can induce bifurcations of the neural firing patterns. The potential role of these bifurcation structures in neural information coding mechanism is discussed.}, - doi = {10.1007/s11431-014-5526-0}, - file = {:Gu2014 - Potassium Induced Bifurcations and Chaos of Firing Patterns Observed from Biological Experiment on a Neural Pacemaker.pdf:PDF}, - keywords = {bifurcation, neural firing pattern, chaos, potassium ion}, - language = {english}, - -} - - -@Article{Zeberg2015, - author = {Zeberg, Hugo and Robinson, Hugh P. C. and Århem, Peter}, - journal = {Journal of Neurophysiology}, - title = {Density of voltage-gated potassium channels is a bifurcation parameter in pyramidal neurons}, - year = {2015}, - issn = {0022-3077}, - month = jan, - number = {2}, - pages = {537--549}, - volume = {113}, - abstract = {Several types of intrinsic dynamics have been identified in brain neurons. Type 1 excitability is characterized by a continuous frequency-stimulus relationship and, thus, an arbitrarily low frequency at threshold current. Conversely, Type 2 excitability is characterized by a discontinuous frequency-stimulus relationship and a nonzero threshold frequency. In previous theoretical work we showed that the density of Kv channels is a bifurcation parameter, such that increasing the Kv channel density in a neuron model transforms Type 1 excitability into Type 2 excitability. Here we test this finding experimentally, using the dynamic clamp technique on Type 1 pyramidal cells in rat cortex. We found that increasing the density of slow Kv channels leads to a shift from Type 1 to Type 2 threshold dynamics, i.e., a distinct onset frequency, subthreshold oscillations, and reduced latency to first spike. In addition, the action potential was resculptured, with a narrower spike width and more pronounced afterhyperpolarization. All changes could be captured with a two-dimensional model. It may seem paradoxical that an increase in slow K channel density can lead to a higher threshold firing frequency; however, this can be explained in terms of bifurcation theory. In contrast to previous work, we argue that an increased outward current leads to a change in dynamics in these neurons without a rectification of the current-voltage curve. These results demonstrate that the behavior of neurons is determined by the global interactions of their dynamical elements and not necessarily simply by individual types of ion channels.}, - doi = {10.1152/jn.00907.2013}, - file = {:Zeberg2015 - Density of Voltage Gated Potassium Channels Is a Bifurcation Parameter in Pyramidal Neurons.pdf:PDF}, - keywords = {bifurcation, dynamic clamp, ion channel density, pyramidal neuron, threshold dynamics}, - publisher = {American Physiological Society}, -} - - -@Article{Aarhem2007, - author = {{\AA}rhem, Peter and Blomberg, Clas}, - journal = {Biosystems}, - title = {Ion channel density and threshold dynamics of repetitive firing in a cortical neuron model}, - year = {2007}, - issn = {0303-2647}, - month = may, - number = {1}, - pages = {117--125}, - volume = {89}, - abstract = {Modifying the density and distribution of ion channels in a neuron (by natural up- and down-regulation, by pharmacological intervention or by spontaneous mutations) changes its activity pattern. In the present investigation, we analyze how the impulse patterns are regulated by the density of voltage-gated channels in a model neuron, based on voltage clamp measurements of hippocampal interneurons. At least three distinct oscillatory patterns, associated with three distinct regions in the Na–K channel density plane, were found. A stability analysis showed that the different regions are characterized by saddle-node, double-orbit, and Hopf bifurcation threshold dynamics, respectively. Single strongly graded action potentials occur in an area outside the oscillatory regions, but less graded action potentials occur together with repetitive firing over a considerable range of channel densities. The presently found relationship between channel densities and oscillatory behavior may be relevance for understanding principal spiking patterns of cortical neurons (regular firing and fast spiking). It may also be of relevance for understanding the action of pharmacological compounds on brain oscillatory activity.}, - doi = {10.1016/j.biosystems.2006.03.015}, - file = {ScienceDirect Full Text PDF:https\://www.sciencedirect.com/science/article/pii/S0303264706002498/pdfft?md5=f5026b3f7f4298030a483889c8b4ac4d&pid=1-s2.0-S0303264706002498-main.pdf&isDTMRedir=Y:application/pdf}, - keywords = {Ion channels, Hopf bifurcation, Saddle-node bifurcation, Hippocampal interneuron, Threshold dynamics}, - language = {english}, - series = {Selected {Papers} presented at the 6th {International} {Workshop} on {Neural} {Coding}}, -} - - -@Article{Qi2013, - author = {Qi, Y. and Watts, A. L. and Kim, J. W. and Robinson, P. A.}, - journal = {Biological Cybernetics}, - title = {Firing patterns in a conductance-based neuron model: bifurcation, phase diagram, and chaos}, - year = {2013}, - issn = {1432-0770}, - month = feb, - number = {1}, - pages = {15--24}, - volume = {107}, - abstract = {Responding to various stimuli, some neurons either remain resting or can fire several distinct patterns of action potentials, such as spiking, bursting, subthreshold oscillations, and chaotic firing. In particular, Wilson’s conductance-based neocortical neuron model, derived from the Hodgkin–Huxley model, is explored to understand underlying mechanisms of the firing patterns. Phase diagrams describing boundaries between the domains of different firing patterns are obtained via extensive numerical computations. The boundaries are further studied by standard instability analyses, which demonstrates that the chaotic neural firing could develop via period-doubling and/or period- adding cascades. Sequences of the firing patterns often observed in many neural experiments are also discussed in the phase diagram framework developed. Our results lay the groundwork for wider use of the model, especially for incorporating it into neural field modeling of the brain.}, - doi = {10.1007/s00422-012-0520-8}, - file = {:Qi2013 - Firing Patterns in a Conductance Based Neuron Model_ Bifurcation, Phase Diagram, and Chaos.pdf:PDF}, - keywords = {Action potential, Conductance-based neuron model, Linear stability analysis, Period-doubling/adding route to chaos}, - language = {english}, - shorttitle = {Firing patterns in a conductance-based neuron model}, -} - - -@Article{Gu2014a, - author = {Gu, Huaguang and Pan, Baobao and Chen, Guanrong and Duan, Lixia}, - journal = {Nonlinear Dynamics}, - title = {Biological experimental demonstration of bifurcations from bursting to spiking predicted by theoretical models}, - year = {2014}, - issn = {1573-269X}, - month = oct, - number = {1}, - pages = {391--407}, - volume = {78}, - abstract = {A series of bifurcations from period-1 bursting to period-1 spiking in a complex (or simple) process were observed with increasing extra-cellular potassium concentration during biological experiments on different neural pacemakers. This complex process is composed of three parts: period-adding sequences of burstings, chaotic bursting to chaotic spiking, and an inverse period-doubling bifurcation of spiking patterns. Six cases of bifurcations with complex processes distinguished by period-adding sequences with stochastic or chaotic burstings that can reach different bursting patterns, and three cases of bifurcations with simple processes, without the transition from chaotic bursting to chaotic spiking, were identified. It reveals the structures closely matching those simulated in a two-dimensional parameter space of the Hindmarsh–Rose model, by increasing one parameter \$\$I\$\$and fixing another parameter \$\$r\$\$at different values. The experimental bifurcations also resembled those simulated in a physiologically based model, the Chay model. The experimental observations not only reveal the nonlinear dynamics of the firing patterns of neural pacemakers but also provide experimental evidence of the existence of bifurcations from bursting to spiking simulated in the theoretical models.}, - doi = {10.1007/s11071-014-1447-5}, - file = {:Gu2014a - Biological Experimental Demonstration of Bifurcations from Bursting to Spiking Predicted by Theoretical Models.pdf:PDF}, - keywords = {Bifurcation, Neural firing, Chaos, Bursting, Spiking, Period-adding bifurcation}, - language = {english}, -} - - -@Article{Zeberg2010, - author = {Zeberg, Hugo and Blomberg, Clas and {\AA}rhem, Peter}, - journal = {PLOS Computational Biology}, - title = {Ion {Channel} {Density} {Regulates} {Switches} between {Regular} and {Fast} {Spiking} in {Soma} but {Not} in {Axons}}, - year = {2010}, - issn = {1553-7358}, - month = apr, - number = {4}, - pages = {e1000753}, - volume = {6}, - abstract = {The threshold firing frequency of a neuron is a characterizing feature of its dynamical behaviour, in turn determining its role in the oscillatory activity of the brain. Two main types of dynamics have been identified in brain neurons. Type 1 dynamics (regular spiking) shows a continuous relationship between frequency and stimulation current (f-Istim) and, thus, an arbitrarily low frequency at threshold current; Type 2 (fast spiking) shows a discontinuous f-Istim relationship and a minimum threshold frequency. In a previous study of a hippocampal neuron model, we demonstrated that its dynamics could be of both Type 1 and Type 2, depending on ion channel density. In the present study we analyse the effect of varying channel density on threshold firing frequency on two well-studied axon membranes, namely the frog myelinated axon and the squid giant axon. Moreover, we analyse the hippocampal neuron model in more detail. The models are all based on voltage-clamp studies, thus comprising experimentally measurable parameters. The choice of analysing effects of channel density modifications is due to their physiological and pharmacological relevance. We show, using bifurcation analysis, that both axon models display exclusively Type 2 dynamics, independently of ion channel density. Nevertheless, both models have a region in the channel-density plane characterized by an N-shaped steady-state current-voltage relationship (a prerequisite for Type 1 dynamics and associated with this type of dynamics in the hippocampal model). In summary, our results suggest that the hippocampal soma and the two axon membranes represent two distinct kinds of membranes; membranes with a channel-density dependent switching between Type 1 and 2 dynamics, and membranes with a channel-density independent dynamics. The difference between the two membrane types suggests functional differences, compatible with a more flexible role of the soma membrane than that of the axon membrane.}, - doi = {10.1371/journal.pcbi.1000753}, - file = {:Zeberg2010 - Ion Channel Density Regulates Switches between Regular and Fast Spiking in Soma but Not in Axons.pdf:PDF}, - keywords = {Axons, Neurons, Hippocampus, Squids, Membrane potential, Action potentials, Ion channels, Behavior}, - language = {english}, - publisher = {Public Library of Science}, -} - - -@Article{Zhou2020, - author = {Zhou, Xiuying and Xu, Ying and Wang, Guowei and Jia, Ya}, - journal = {Cognitive Neurodynamics}, - title = {Ionic channel blockage in stochastic {Hodgkin}–{Huxley} neuronal model driven by multiple oscillatory signals}, - year = {2020}, - issn = {1871-4099}, - month = aug, - number = {4}, - pages = {569--578}, - volume = {14}, - abstract = {Ionic channel blockage and multiple oscillatory signals play an important role in the dynamical response of pulse sequences. The effects of ionic channel blockage and ionic channel noise on the discharge behaviors are studied in Hodgkin–Huxley neuronal model with multiple oscillatory signals. It is found that bifurcation points of spontaneous discharge are altered through tuning the amplitude of multiple oscillatory signals, and the discharge cycle is changed by increasing the frequency of multiple oscillatory signals. The effects of ionic channel blockage on neural discharge behaviors indicate that the neural excitability can be suppressed by the sodium channel blockage, however, the neural excitability can be reversed by the potassium channel blockage. There is an optimal blockage ratio of potassium channel at which the electrical activity is the most regular, while the order of neural spike is disrupted by the sodium channel blockage. In addition, the frequency of spike discharge is accelerated by increasing the ionic channel noise, the firing of neuron becomes more stable if the ionic channel noise is appropriately reduced. Our results might provide new insights into the effects of ionic channel blockages, multiple oscillatory signals, and ionic channel noises on neural discharge behaviors.}, - doi = {10.1007/s11571-020-09593-7}, - file = {:Zhou2020 - Ionic Channel Blockage in Stochastic Hodgkin–Huxley Neuronal Model Driven by Multiple Oscillatory Signals.pdf:PDF}, - keywords = {Ionic channel blockage, Stochastic Hodgkin–Huxley model, Multiple oscillatory signal, Discharge behavior}, - language = {english}, -} - - -@Article{Whittaker2020, - author = {Whittaker, Dominic G. and Clerx, Michael and Lei, Chon Lok and Christini, David J. and Mirams, Gary R.}, - journal = {WIREs Systems Biology and Medicine}, - title = {Calibration of ionic and cellular cardiac electrophysiology models}, - year = {2020}, - issn = {1939-005X}, - number = {4}, - pages = {e1482}, - volume = {12}, - abstract = {Cardiac electrophysiology models are among the most mature and well-studied mathematical models of biological systems. This maturity is bringing new challenges as models are being used increasingly to make quantitative rather than qualitative predictions. As such, calibrating the parameters within ion current and action potential (AP) models to experimental data sets is a crucial step in constructing a predictive model. This review highlights some of the fundamental concepts in cardiac model calibration and is intended to be readily understood by computational and mathematical modelers working in other fields of biology. We discuss the classic and latest approaches to calibration in the electrophysiology field, at both the ion channel and cellular AP scales. We end with a discussion of the many challenges that work to date has raised and the need for reproducible descriptions of the calibration process to enable models to be recalibrated to new data sets and built upon for new studies. This article is categorized under: Analytical and Computational Methods {\textgreater} Computational Methods Physiology {\textgreater} Mammalian Physiology in Health and Disease Models of Systems Properties and Processes {\textgreater} Cellular Models}, - doi = {10.1002/wsbm.1482}, - file = {Full Text PDF:https\://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/wsbm.1482:application/pdf}, - keywords = {cardiac, electrophysiology, identification, inference, mathematical modeling, optimization, parameterization}, - language = {english}, - -} - -@Article{Browne1994, - author = {Browne, David L. and Gancher, Stephen T. and Nutt, John G. and Brunt, Ewout R. P. and Smith, Eric A. and Kramer, Patricia and Litt, Michael}, - journal = {Nature Genetics}, - title = {Episodic ataxia/myokymia syndrome is associated with point mutations in the human potassium channel gene, {KCNA1}}, - year = {1994}, - issn = {1546-1718}, - month = oct, - number = {2}, - pages = {136--140}, - volume = {8}, - abstract = {Episodic ataxia (EA) is a rare, familial disorder producing attacks of generalized ataxia, with normal or near-normal neurological function between attacks. One type of EA is characterized by brief episodes of ataxia with myokymia (rippling of muscles) evident between attacks. Linkage studies in four such families suggested localization of an EA/ myokymia gene near the voltage gated K+ channel gene, KCNA1 (Kv1.1), on chromosome 12p. Mutation analysis of the KCNA1 coding region in these families identified four different missense point mutations present in the heterozygous state, indicating that EA/myokymia can result from mutations in this gene.}, - copyright = {1994 Nature Publishing Group}, - doi = {10.1038/ng1094-136}, - file = {Full Text PDF:C\:\\Users\\nilsk\\Zotero\\storage\\WKWMG5CL\\Browne et al. - 1994 - Episodic ataxiamyokymia syndrome is associated wi.pdf:application/pdf;Full Text PDF:C\:\\Users\\nilsk\\Zotero\\storage\\UZJSGF2J\\Browne et al. - 1994 - Episodic ataxiamyokymia syndrome is associated wi.pdf:application/pdf;Snapshot:C\:\\Users\\nilsk\\Zotero\\storage\\H7HS6X9W\\ng1094-136.html:text/html;Snapshot:C\:\\Users\\nilsk\\Zotero\\storage\\JUTGMKPM\\ng1094-136.html:text/html}, - language = {english}, - urldate = {2021-06-10}, -} - -@Article{Browne1995, - author = {Browne, D.L. and Brunt, E.R.P. and Griggs, R.C. and Nutt, J.G. and Gancher, S.T. and Smith, E.A. and Litt, M.}, - journal = {Human Molecular Genetics}, - title = {Identification of two new {KCNA1} mutations in episodic ataxia/myokymia families}, - year = {1995}, - issn = {0964-6906}, - month = sep, - number = {9}, - pages = {1671--1672}, - volume = {4}, - doi = {10.1093/hmg/4.9.1671}, - file = {Full Text PDF:C\:\\Users\\nilsk\\Zotero\\storage\\X8R57337\\Browne et al. - 1995 - Identification of two new KCNA1 mutations in episo.pdf:application/pdf;Snapshot:C\:\\Users\\nilsk\\Zotero\\storage\\X8SUGSSL\\635268.html:text/html}, - urldate = {2021-06-10}, -} - - -@Article{Hedrich2021, - author = {Hedrich, Ulrike B. S. and Lauxmann, Stephan and Wolff, Markus and Synofzik, Matthis and Bast, Thomas and Binelli, Adrian and Serratosa, José M. and Martínez-Ulloa, Pedro and Allen, Nicholas M. and King, Mary D. and Gorman, Kathleen M. and Zeev, Bruria Ben and Tzadok, Michal and Wong-Kisiel, Lily and Marjanovic, Dragan and Rubboli, Guido and Sisodiya, Sanjay M. and Lutz, Florian and Ashraf, Harshad Pannikkaveettil and Torge, Kirsten and Yan, Pu and Bosselmann, Christian and Schwarz, Niklas and Fudali, Monika and Lerche, Holger}, - journal = {Science Translational Medicine}, - title = {4-{Aminopyridine} is a promising treatment option for patients with gain-of-function {KCNA2}-encephalopathy}, - year = {2021}, - month = sep, - number = {609}, - pages = {eaaz4957}, - volume = {13}, - doi = {10.1126/scitranslmed.aaz4957}, - file = {Full Text PDF:https\://www.science.org/doi/pdf/10.1126/scitranslmed.aaz4957:application/pdf}, - publisher = {American Association for the Advancement of Science}, - urldate = {2022-09-02}, -} - - -@Article{Colasante2020, - author = {Colasante, Gaia and Lignani, Gabriele and Brusco, Simone and Di Berardino, Claudia and Carpenter, Jenna and Giannelli, Serena and Valassina, Nicholas and Bido, Simone and Ricci, Raffaele and Castoldi, Valerio and Marenna, Silvia and Church, Timothy and Massimino, Luca and Morabito, Giuseppe and Benfenati, Fabio and Schorge, Stephanie and Leocani, Letizia and Kullmann, Dimitri M. and Broccoli, Vania}, - journal = {Molecular Therapy}, - title = {{dCas9}-{Based} {Scn1a} {Gene} {Activation} {Restores} {Inhibitory} {Interneuron} {Excitability} and {Attenuates} {Seizures} in {Dravet} {Syndrome} {Mice}}, - year = {2020}, - issn = {1525-0016}, - month = jan, - number = {1}, - pages = {235--253}, - volume = {28}, - abstract = {Dravet syndrome (DS) is a severe epileptic encephalopathy caused mainly by heterozygous loss-of-function mutations of the SCN1A gene, indicating haploinsufficiency as the pathogenic mechanism. Here we tested whether catalytically dead Cas9 (dCas9)-mediated Scn1a gene activation can rescue Scn1a haploinsufficiency in a mouse DS model and restore physiological levels of its gene product, the Nav1.1 voltage-gated sodium channel. We screened single guide RNAs (sgRNAs) for their ability to stimulate Scn1a transcription in association with the dCas9 activation system. We identified a specific sgRNA that increases Scn1a gene expression levels in cell lines and primary neurons with high specificity. Nav1.1 protein levels were augmented, as was the ability of wild-type immature GABAergic interneurons to fire action potentials. A similar enhancement of Scn1a transcription was achieved in mature DS interneurons, rescuing their ability to fire. To test the therapeutic potential of this approach, we delivered the Scn1a-dCas9 activation system to DS pups using adeno-associated viruses. Parvalbumin interneurons recovered their firing ability, and febrile seizures were significantly attenuated. Our results pave the way for exploiting dCas9-based gene activation as an effective and targeted approach to DS and other disorders resulting from altered gene dosage.}, - doi = {10.1016/j.ymthe.2019.08.018}, - file = {:colasante_dcas9-based_2020 - DCas9 Based Scn1a Gene Activation Restores Inhibitory Interneuron Excitability and Attenuates Seizures in Dravet Syndrome Mice.html:URL}, - keywords = {gene therapy, Dravet syndrome, epileptic encephalopathy, activatory CRISPR}, - language = {english}, - urldate = {2022-09-03}, -} - - -@Article{Yu2006, - author = {Yu, Frank H. and Mantegazza, Massimo and Westenbroek, Ruth E. and Robbins, Carol A. and Kalume, Franck and Burton, Kimberly A. and Spain, William J. and McKnight, G. Stanley and Scheuer, Todd and Catterall, William A.}, - journal = {Nature Neuroscience}, - title = {Reduced sodium current in {GABAergic} interneurons in a mouse model of severe myoclonic epilepsy in infancy}, - year = {2006}, - issn = {1546-1726}, - month = sep, - number = {9}, - pages = {1142--1149}, - volume = {9}, - abstract = {Voltage-gated sodium channels (NaV) are critical for initiation of action potentials. Heterozygous loss-of-function mutations in NaV1.1 channels cause severe myoclonic epilepsy in infancy (SMEI). Homozygous null Scn1a−/− mice developed ataxia and died on postnatal day (P) 15 but could be sustained to P17.5 with manual feeding. Heterozygous Scn1a+/− mice had spontaneous seizures and sporadic deaths beginning after P21, with a notable dependence on genetic background. Loss of NaV1.1 did not change voltage-dependent activation or inactivation of sodium channels in hippocampal neurons. The sodium current density was, however, substantially reduced in inhibitory interneurons of Scn1a+/− and Scn1a−/− mice but not in their excitatory pyramidal neurons. An immunocytochemical survey also showed a specific upregulation of NaV1.3 channels in a subset of hippocampal interneurons. Our results indicate that reduced sodium currents in GABAergic inhibitory interneurons in Scn1a+/− heterozygotes may cause the hyperexcitability that leads to epilepsy in patients with SMEI.}, - copyright = {2006 Nature Publishing Group}, - doi = {10.1038/nn1754}, - file = {:Yu2006 - Reduced Sodium Current in GABAergic Interneurons in a Mouse Model of Severe Myoclonic Epilepsy in Infancy.html:URL}, - keywords = {Biomedicine, general, Neurosciences, Behavioral Sciences, Biological Techniques, Neurobiology, Animal Genetics and Genomics}, - language = {english}, - publisher = {Nature Publishing Group}, - urldate = {2022-09-03}, -} - -@InBook{Rinzel_1998, - author = {John Rinzel and GB Ermentrout}, - editor = {C Koch and I Segev}, - pages = {135--169}, - publisher = {MIT Press}, - title = {Analysis of neural excitability and oscillations}, - year = {1989}, - booktitle = {Methods in neuronal modeling}, - language = {english}, -} - - -@Article{Claes2001, - author = {Claes, Lieve and Del-Favero, Jurgen and Ceulemans, Berten and Lagae, Lieven and Van Broeckhoven, Christine and De Jonghe, Peter}, - journal = {The American Journal of Human Genetics}, - title = {De {Novo} {Mutations} in the {Sodium}-{Channel} {Gene} {SCN1A} {Cause} {Severe} {Myoclonic} {Epilepsy} of {Infancy}}, - year = {2001}, - issn = {0002-9297}, - month = jun, - number = {6}, - pages = {1327--1332}, - volume = {68}, - abstract = {Severe myoclonic epilepsy of infancy (SMEI) is a rare disorder that occurs in isolated patients. The disease is characterized by generalized tonic, clonic, and tonic-clonic seizures that are initially induced by fever and begin during the first year of life. Later, patients also manifest other seizure types, including absence, myoclonic, andsimple and complex partial seizures. Psychomotor development stagnates around the second year of life. Missense mutations in the gene that codes for a neuronal voltage-gated sodium-channel α-subunit (SCN1A) were identified in families with generalized epilepsy with febrile seizures plus (GEFS+). GEFS+ is a mild type of epilepsy associated with febrile and afebrile seizures. Because both GEFS+ and SMEI involve fever-associated seizures, we screened seven unrelated patients with SMEI for mutations in SCN1A. We identified a mutation in each patient: four had frameshift mutations, one had a nonsense mutation, one had a splice-donor mutation, and one had a missense mutation. All mutations are de novo mutations and were not observed in 184 control chromosomes.}, - doi = {10.1086/320609}, - file = {:claes_novo_2001 - De Novo Mutations in the Sodium Channel Gene SCN1A Cause Severe Myoclonic Epilepsy of Infancy.html:URL}, - language = {english}, - urldate = {2022-09-22}, -} - - -@Article{Oguni2001, - author = {Oguni, Hirokazu and Hayashi, Kitami and Awaya, Yutaka and Fukuyama, Yukio and Osawa, Makiko}, - journal = {Brain and Development}, - title = {Severe myoclonic epilepsy in infants – a review based on the {Tokyo} {Women}'s {Medical} {University} series of 84 cases}, - year = {2001}, - issn = {0387-7604}, - month = nov, - number = {7}, - pages = {736--748}, - volume = {23}, - abstract = {Severe myoclonic epilepsy in infants (SME) is one of the most malignant epileptic syndromes recognized in the latest classification of epileptic syndromes. The clinical details and electroencephalographic (EEG) characteristics have been elucidated by Dravet et al. The diagnosis of SME depends largely on the combination of clinical and EEG manifestations at different ages, of which the presence of myoclonic seizures appears to be the most important. However, because of the inclusion of different types of myoclonic attack and the lack of strict criteria for diagnosing SME, there has been some confusion as to whether patients without myoclonic seizures or myoclonus should be classified as SME, despite other identical clinical symptoms (SME borderlands (SMEB) group). Among the various clinical manifestations characterizing SME, special attention has been paid to seizures easily precipitated by fever and hot baths in Japan. We have demonstrated that the onset of myoclonic attack in these patients is very sensitive to the elevation of body temperature itself rather than its etiology. Using simultaneous EEG and rectal temperature monitoring during hot water immersion, we showed that epileptic discharges increased in frequency, and eventually developed into seizures at temperatures over 38°C. We believe that the unique fever sensitivity observed in SME is similar to, but more intense than that of febrile convulsions. We have also identified a group of cases who have had innumerous myoclonic and atypical absence seizures daily which were sensitive to the constant bright light illumination. In these cases, spike discharges increased or decreased depending on the intensity of constant light illumination. Although these cases form the most resistant SME group, they lost the constant light sensitivity with increasing age, leaving only relatively common types of fever-sensitive grand mal seizures (FSGM) at the age of around 5 years. In the long run, only convulsive seizures continue, while myoclonic or absence seizures and photosensitivity disappear with advancing age, thus it is conceivable that SMEB constitutes a basic epileptic condition underlying SME. There is a clinical continuum that extends from the mildest end of SMEB to the severest end of SME with constant light sensitivity, with intermediates of frequent or infrequent myoclonic and absence seizures in-between. This spectrum concept appropriately explains the clinical variabilities between SME and SMEB during early childhood.}, - doi = {10.1016/S0387-7604(01)00276-5}, - file = {:Oguni2001 - Severe Myoclonic Epilepsy in Infants – a Review Based on the Tokyo Women's Medical University Series of 84 Cases.html:URL}, - keywords = {Severe myoclonic epilepsy in infants, Borderland group, Myoclonic seizures, Myoclonus, Fever sensitivity, Fever-sensitive grand mal, Constant light sensitivity}, - language = {english}, - series = {West {Syndrome} and {Other} {Infantile} {Epileptic} {Encephalopathies}}, - urldate = {2022-09-22}, -} - - -@Article{Fujiwara2003, - author = {Fujiwara, Tateki and Sugawara, Takashi and Mazaki‐Miyazaki, Emi and Takahashi, Yukitoshi and Fukushima, Katsuyuki and Watanabe, Masako and Hara, Keita and Morikawa, Tateki and Yagi, Kazuichi and Yamakawa, Kazuhiro and Inoue, Yushi}, - journal = {Brain}, - title = {Mutations of sodium channel α subunit type 1 ({SCN1A}) in intractable childhood epilepsies with frequent generalized tonic–clonic seizures}, - year = {2003}, - issn = {0006-8950}, - month = mar, - number = {3}, - pages = {531--546}, - volume = {126}, - abstract = {A group of infant onset epilepsies manifest very frequent generalized tonic–clonic seizures (GTC) intractable to medical therapy, which may or may not be accompanied by minor seizures such as myoclonic seizures, absences and partial seizures. They include severe myoclonic epilepsy in infancy (SMEI) and intractable childhood epilepsy with GTC (ICEGTC). They are commonly associated with fever‐sensitivity, family history of seizure disorders and developmental decline after seizure onset. Mutations of the neuronal voltage‐gated sodium channel α subunit type 1 gene (SCN1A) were recently reported in SMEI patients. To clarify the genotypic differences in this group of epilepsies, we searched for SCN1A abnormalities in 25 patients with SMEI and 10 with ICEGTC, together with the family members of 15 patients. Frameshift mutations in SCN1A were observed in four patients, nonsense mutations in five patients, missense mutations in 21 patients, other mutations in two patients and no mutation in five patients. SMEI patients showed nonsense mutations, frameshifts, or missense mutations, while ICEGTC patients showed only missense mutations. Study of both parents of 11 patients revealed that the mutations in these patients were de novo. However, two mothers had the same missense mutations as their ICEGTC children, and they had generalized epilepsy with febrile seizures plus. Here we suggest that SMEI and ICEGTC represent a continuum with minor phenotypic and genotypic differences.}, - doi = {10.1093/brain/awg053}, - file = {:Fujiwara2003 - Mutations of Sodium Channel Α Subunit Type 1 (SCN1A) in Intractable Childhood Epilepsies with Frequent Generalized Tonic–clonic Seizures.html:URL}, - urldate = {2022-09-22}, -} - - -@Article{Ohmori2002, - author = {Ohmori, Iori and Ouchida, Mamoru and Ohtsuka, Yoko and Oka, Eiji and Shimizu, Kenji}, - journal = {Biochemical and Biophysical Research Communications}, - title = {Significant correlation of the {SCN1A} mutations and severe myoclonic epilepsy in infancy}, - year = {2002}, - issn = {0006-291X}, - month = jul, - number = {1}, - pages = {17--23}, - volume = {295}, - abstract = {To investigate the possible correlation between genotype and phenotype of epilepsy, we analyzed the voltage-gated sodium channel α1-subunit (SCN1A) gene, β1-subunit (SCN1B) gene, and γ-aminobutyric acidA receptor γ2-subunit (GABRG2) gene in DNAs from peripheral blood cells of 29 patients with severe myoclonic epilepsy in infancy (SME) and 11 patients with other types of epilepsy. Mutations of the SCN1A gene were detected in 24 of the 29 patients (82.7\%) with SME, although none with other types of epilepsy. The mutations included deletion, insertion, missense, and nonsense mutations. We could not find any mutations of the SCN1B and GABRG2 genes in all patients. Our data suggested that the SCN1A mutations were significantly correlated with SME (p{\textless}.0001). As we could not find SCN1A mutations in their parents, one of critical causes of SME may be de novo mutation of the SCN1A gene occurred in the course of meiosis in the parents.}, - doi = {10.1016/S0006-291X(02)00617-4}, - file = {:Ohmori2002 - Significant Correlation of the SCN1A Mutations and Severe Myoclonic Epilepsy in Infancy.html:URL}, - keywords = {Neuronal voltage-gated sodium channel, SCN1A, SCN1B, GABRG2, Generalized epilepsy with febrile seizures plus, Sever myoclonic epilepsy in infancy}, - language = {english}, - urldate = {2022-09-22}, -} - - -@Article{OLeary2016, - author = {O’Leary, Timothy and Marder, Eve}, - journal = {Current Biology}, - title = {Temperature-{Robust} {Neural} {Function} from {Activity}-{Dependent} {Ion} {Channel} {Regulation}}, - year = {2016}, - issn = {0960-9822}, - month = nov, - number = {21}, - pages = {2935--2941}, - volume = {26}, - abstract = {Many species of cold-blooded animals experience substantial and rapid fluctuations in body temperature. Because biological processes are differentially temperature dependent, it is difficult to understand how physiological processes in such animals can be temperature robust [1, 2, 3, 4, 5, 6, 7, 8]. Experiments have shown that core neural circuits, such as the pyloric circuit of the crab stomatogastric ganglion (STG), exhibit robust neural activity in spite of large (20°C) temperature fluctuations [3, 5, 7, 8]. This robustness is surprising because (1) each neuron has many different kinds of ion channels with different temperature dependencies (Q10s) that interact in a highly nonlinear way to produce firing patterns and (2) across animals there is substantial variability in conductance densities that nonetheless produce almost identical firing properties. The high variability in conductance densities in these neurons [9, 10] appears to contradict the possibility that robustness is achieved through precise tuning of key temperature-dependent processes. In this paper, we develop a theoretical explanation for how temperature robustness can emerge from a simple regulatory control mechanism that is compatible with highly variable conductance densities [11, 12, 13]. The resulting model suggests a general mechanism for how nervous systems and excitable tissues can exploit degenerate relationships among temperature-sensitive processes to achieve robust function.}, - doi = {10.1016/j.cub.2016.08.061}, - file = {:O’Leary2016 - Temperature Robust Neural Function from Activity Dependent Ion Channel Regulation.html:URL}, - keywords = {ion channels, homeostatic plasticity, temperature compensation, computational model, mathematical model, neuronal excitability, stomatogastric ganglion, crustacean, central pattern generator}, - language = {english}, - urldate = {2022-09-25}, -} - - -@Article{Masnada2017, - author = {Masnada, Silvia and Hedrich, Ulrike B S and Gardella, Elena and Schubert, Julian and Kaiwar, Charu and Klee, Eric W and Lanpher, Brendan C and Gavrilova, Ralitza H and Synofzik, Matthis and Bast, Thomas and Gorman, Kathleen and King, Mary D and Allen, Nicholas M and Conroy, Judith and Ben Zeev, Bruria and Tzadok, Michal and Korff, Christian and Dubois, Fanny and Ramsey, Keri and Narayanan, Vinodh and Serratosa, Jose M and Giraldez, Beatriz G and Helbig, Ingo and Marsh, Eric and O’Brien, Margaret and Bergqvist, Christina A and Binelli, Adrian and Porter, Brenda and Zaeyen, Eduardo and Horovitz, Dafne D and Wolff, Markus and Marjanovic, Dragan and Caglayan, Hande S and Arslan, Mutluay and Pena, Sergio D J and Sisodiya, Sanjay M and Balestrini, Simona and Syrbe, Steffen and Veggiotti, Pierangelo and Lemke, Johannes R and Møller, Rikke S and Lerche, Holger and Rubboli, Guido}, - journal = {Brain}, - title = {Clinical spectrum and genotype–phenotype associations of {KCNA2}-related encephalopathies}, - year = {2017}, - issn = {0006-8950}, - month = sep, - number = {9}, - pages = {2337--2354}, - volume = {140}, - abstract = {Recently, de novo mutations in the gene KCNA2, causing either a dominant-negative loss-of-function or a gain-of-function of the voltage-gated K+ channel Kv1.2, were described to cause a new molecular entity within the epileptic encephalopathies. Here, we report a cohort of 23 patients (eight previously described) with epileptic encephalopathy carrying either novel or known KCNA2 mutations, with the aim to detail the clinical phenotype associated with each of them, to characterize the functional effects of the newly identified mutations, and to assess genotype–phenotype associations. We identified five novel and confirmed six known mutations, three of which recurred in three, five and seven patients, respectively. Ten mutations were missense and one was a truncation mutation; de novo occurrence could be shown in 20 patients. Functional studies using a Xenopus oocyte two-microelectrode voltage clamp system revealed mutations with only loss-of-function effects (mostly dominant-negative current amplitude reduction) in eight patients or only gain-of-function effects (hyperpolarizing shift of voltage-dependent activation, increased amplitude) in nine patients. In six patients, the gain-of-function was diminished by an additional loss-of-function (gain-and loss-of-function) due to a hyperpolarizing shift of voltage-dependent activation combined with either decreased amplitudes or an additional hyperpolarizing shift of the inactivation curve. These electrophysiological findings correlated with distinct phenotypic features. The main differences were (i) predominant focal (loss-of-function) versus generalized (gain-of-function) seizures and corresponding epileptic discharges with prominent sleep activation in most cases with loss-of-function mutations; (ii) more severe epilepsy, developmental problems and ataxia, and atrophy of the cerebellum or even the whole brain in about half of the patients with gain-of-function mutations; and (iii) most severe early-onset phenotypes, occasionally with neonatal onset epilepsy and developmental impairment, as well as generalized and focal seizures and EEG abnormalities for patients with gain- and loss-of-function mutations. Our study thus indicates well represented genotype–phenotype associations between three subgroups of patients with KCNA2 encephalopathy according to the electrophysiological features of the mutations.}, - doi = {10.1093/brain/awx184}, - file = {:Masnada2017 - Clinical Spectrum and Genotype–phenotype Associations of KCNA2 Related Encephalopathies.pdf:PDF}, - urldate = {2022-10-03}, -} - -@Comment{jabref-meta: databaseType:bibtex;}