Changed some minor things in introduction

manuscript.tex

@@ -120,7 +120,11 @@ Although the effects of channelopathies on ion current kinetics are frequently a
 
 
 %General understanding of the effects of changes in current properties on neuronal firing may help to fill the need to understand the impacts of ion channel mutations on neuronal firing. 
-However the effect of a given channelopathy on different neuronal types across the brain is often unclear and not feasible to experimentally obtain. Different neuron types have different ion current compositions \textcolor{red}{(cite Berens and Allan Institute)} and therefore likely respond differently to changes in the properties of one current. In the simplest case, the influence on the firing behaviour should correlate with the expression level of the affected gene \textcolor{red}{(cite Niko, other Papers)}. But if a\textcolor{red}{ kinetic parameter} is changed too much, it can have unforseen consequences. For instance, altering relative current amplitudes can dramatically influence the firing behaviour and dynamics of neurons \citep{rutecki_neuronal_1992, pospischil_minimal_2008,Kispersky2012, golowasch_failure_2002, barreiro_-current_2012, Noebels2017, Layer2021}, however other current parameters impact neuronal firing as well. In extreme cases, a mutation can have opposite effects on different neuron types. For example, the R1629H SCN1A mutation is associated which increased firing in interneurons, but decreases pyramidal neuron excitability \citep{Hedrich14874}\textcolor{red}{(and the other paper?)}. 
+However the effect of a given channelopathy on different neuronal types across the brain is often unclear and not feasible to experimentally obtain. Different neuron types have different ion current compositions \textcolor{red}{(cite Berens and Allan Institute)} and therefore likely respond differently to changes in the properties of one current.
+% \textcolor{red}{In the simplest case, the influence on the firing behaviour should correlate with the expression level of the affected gene \textcolor{red}{(cite Niko , other Papers)}. But if a \textcolor{red}{ kinetic parameter} is changed too much, it can have unforseen consequences. }
+  The expression level of an affected gene can correlate with firing behaviour in the simplest case \textcolor{red}{(cite Niko - this one \citep{Layer2021}?, other Papers)}, however if a gating property is altered substantially this can have complex consequences.
+
+For instance, altering relative current amplitudes can dramatically influence the firing behaviour and dynamics of neurons \citep{rutecki_neuronal_1992, pospischil_minimal_2008,Kispersky2012, golowasch_failure_2002, barreiro_-current_2012, Noebels2017, Layer2021}, however other current parameters impact neuronal firing as well. In extreme cases, a mutation can have opposite effects on different neuron types. For example, the R1629H SCN1A mutation is associated which increased firing in interneurons, but decreases pyramidal neuron excitability \citep{Hedrich14874}\textcolor{red}{(and the other paper?)}.  %not sure which paper you mean Lukas
 
 %However, the effect on the firing behaviour of different neurons is often unclear \textcolor{red}{(and always incomplete)}. Generally, different neuron types have different ionic current compositions and therefore could react in different ways to changes in one ionic current. In the simpler cases, the respective firing behaviour should mostly correlate with expression level of the affected current and scale with it \textcolor{red}{(cite some stuff, cite NikoPaper)}. \textcolor{red}{If the change in gating kinetics is too strong, the firing behaviour can change qualitatively.} Altering the relative current amplitudes in neuronal models leads to dramtic changes in their firing behaviour and dynamics \citep{rutecki_neuronal_1992, pospischil_minimal_2008,Kispersky2012, golowasch_failure_2002, barreiro_-current_2012, Noebels2017}. \textcolor{red}{The same could happen for other parameters too. \citet{Liu2019} reported a drastically slowed inacitvaiton time constant for a mutation in \textcolor{red}{Na$_V$1.6}, which led to huge depolarization plateaus after an action potential, that lasted several 100 milliseconds.} The most drastic example known to us would be the R1629H mutation in \textcolor{red}{SCN2A}. This mutation increases the excitability of interneurons, but decreases it in pyramidal neurons \textcolor{red}{(cite Hedrich2014 and the other paper)}. \textcolor{red}{Some neuron types may be closer to certain transitions between firing states than other, making these observations even more unpredictable \textcolor{red}{(cite some bifurcation stuff?)}.}
 

ref.bib

@@ -1390,17 +1390,5 @@ SIGNIFICANCE: Bromide is most effective and is a well-tolerated drug among DS pa
 }
 
 
-@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.},
-  file     = {Full Text PDF:https\://www.frontiersin.org/articles/10.3389/fncel.2021.754530/pdf:application/pdf},
-  url      = {https://www.frontiersin.org/article/10.3389/fncel.2021.754530},
-  urldate  = {2022-04-27},
-}
 
 @Comment{jabref-meta: databaseType:bibtex;}