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@ -196,19 +196,19 @@ Although the genetic nature of ion channel mutations as well as their effects on
\par\null
\section*{Introduction (750 Words Maximum - Currently 882 ** with additions in \textcolor{red}{red} and deletions in \textit{italics}: 821)}
\section*{Introduction (750 Words Maximum - Currently 882 ** with additions in \textcolor{red}{red} and deletions in \textit{italics}: 807)}
%\textit{The Introduction should briefly indicate the objectives of the study and provide enough background information to clarify why the study was undertaken and what hypotheses were tested.}
The properties and combinations of voltage-gated ion channels are vital in determining \textit{action potential generation, neuronal firing properties and excitability} \textcolor{red}{neuronal excitability.} \citep{bernard_channelopathies_2008, carbone_ion_2020, rutecki_neuronal_1992, pospischil_minimal_2008}. \textit{However, ion channel function can be disturbed, for instance through genetic alterations, resulting in altered neuronal firing behavior \citep{carbone_ion_2020}}. In recent years, next generation sequencing has led to an increasing number of clinically relevant \textcolor{red}{ ion channels mutations} \textit{genetic mutations} and has provided the basis for pathophysiological studies of genetic epilepsies, pain disorders, dyskinesias, intellectual disabilities, myotonias, and periodic paralyses \citep{bernard_channelopathies_2008, carbone_ion_2020}. Ongoing efforts of many research groups have contributed to the current understanding of underlying disease mechanism in channelopathies, however a complex pathophysiological landscape has emerged for many channelopathies and is likely a reason for limited therapeutic success with standard care.
The effects of mutations in ion channel genes on ionic current kinetics are frequently assessed using heterologous expression systems \textcolor{red}{not expressing} \textit{which do not express} endogenous currents \citep{Balestrini1044, Noebels2017, Dunlop2008}. Ion channel variants are frequently classified as either a loss of function (LOF) or a gain of function (GOF) with respect to changes in \textcolor{red}{ionic current} \textit{gating of the altered ion channels} \citep{Musto2020, Kullmann2002, Waxman2011, Kim2021}. This classification of the effects on ionic currents is often directly used to predict the effects on neuronal firing \citep{Niday2018, Wei2017, Wolff2017,Masnada2017}, which in turn is important for understanding the pathophysiology of these disorders and for identification of potential therapeutic targets \citep{Orsini2018, Yang2018, Colasante2020, Yu2006}. \textcolor{red}{However, the understanding of these complex genotype-phenotype relationships is still evolving \citep{Wolff2017, johannesen_genotype-phenotype_2021}.} \textit{Genotype-phenotype relationships are complex and the understanding of the relationships between these is still evolving \citep{Wolff2017, johannesen_genotype-phenotype_2021}.} Experimentally, the effects of channelopathies on neuronal firing can be assessed using primary neuronal cultures \citep{Scalmani2006, Smith2018, Liu2019} or \textit{in vitro} recordings from slices of transgenic mouse lines \citep{Mantegazza2019, Xie2010,Lory2020, Habib2015, Hedrich14874}. However, the effect of a given channelopathy on the firing behavior of different neuronal types across the brain is often unclear and not feasible to obtain experimentally. Different neuron types differ in their composition of ionic currents \citep{yao2021taxonomy, Cadwell2016, BICCN2021, Scala2021} and therefore likely respond differently to changes in the properties of a single ionic current. For example, the expression level of an affected gene can correlate with firing behavior \textit{in the simplest case} \citep{Layer2021} and altering relative amplitudes of ionic currents can dramatically influence the firing behavior and dynamics of neurons \citep{rutecki_neuronal_1992, pospischil_minimal_2008,Kispersky2012, golowasch_failure_2002, barreiro_-current_2012}. Cell-type specific effects on firing have been experimentally observed. For example, the firing effects of the R1648H \textit{SCN1A} and R1627H \textit{SCN8A} mutations are different in interneurons and pyramidal neurons \citep{Hedrich14874, makinson_scn1a_2016}.
The effects of mutations in ion channel genes on ionic current kinetics are frequently assessed using heterologous expression systems \textcolor{red}{not expressing} \textit{which do not express} endogenous currents \citep{Balestrini1044, Noebels2017, Dunlop2008}. Ion channel variants are frequently classified as either a loss of function (LOF) or a gain of function (GOF) with respect to changes in \textcolor{red}{ionic current} \textit{gating of the altered ion channels} \citep{Musto2020, Kullmann2002, Waxman2011, Kim2021} \textit{. This classification of the effects on ionic currents} \textcolor{red}{This LOF/GOF classification} is often directly used to predict the effects on neuronal firing \citep{Niday2018, Wei2017, Wolff2017,Masnada2017}, which in turn is important for understanding the pathophysiology of these disorders and for identification of potential therapeutic targets \citep{Orsini2018, Yang2018, Colasante2020, Yu2006}. \textcolor{red}{However, the understanding of these complex genotype-phenotype relationships is still evolving \citep{Wolff2017, johannesen_genotype-phenotype_2021}.} \textit{Genotype-phenotype relationships are complex and the understanding of the relationships between these is still evolving \citep{Wolff2017, johannesen_genotype-phenotype_2021}.} Experimentally, the effects of channelopathies on neuronal firing can be assessed using primary neuronal cultures \citep{Scalmani2006, Smith2018, Liu2019} or \textit{in vitro} recordings from slices of transgenic mouse lines \citep{Mantegazza2019, Xie2010,Lory2020, Habib2015, Hedrich14874}. However, the effect of a given channelopathy on the firing behavior of different neuronal types across the brain is often unclear and not feasible to obtain experimentally. Different neuron types differ in their composition of ionic currents \citep{yao2021taxonomy, Cadwell2016, BICCN2021, Scala2021} and therefore likely respond differently to changes in the properties of a single ionic current. \textit{For example, the expression level of an affected gene can correlate with firing behavior \textit{in the simplest case} \citep{Layer2021} and altering relative amplitudes of ionic currents can dramatically influence the firing behavior and dynamics of neurons \citep{rutecki_neuronal_1992, pospischil_minimal_2008,Kispersky2012, golowasch_failure_2002, barreiro_-current_2012}.}\textcolor{red}{Expression level of an affected gene \citep{Layer2021} and relative amplitudes of ionic currents \citep{rutecki_neuronal_1992, pospischil_minimal_2008,Kispersky2012, golowasch_failure_2002, barreiro_-current_2012} can dramatically influence the firing behavior and dynamics of neurons.} Cell-type specific effects on firing have been experimentally observed. For example, the firing effects of the R1648H \textit{SCN1A} and R1627H \textit{SCN8A} mutations are different in interneurons and pyramidal neurons \citep{Hedrich14874, makinson_scn1a_2016}.
%However, if gating kinetics are affected this can have complex consequences on the firing behavior of a specific cell type and the network activity within the brain.
%Altering relative amplitudes of ionic currents can dramatically influence the firing behavior and dynamics of neurons \citep{rutecki_neuronal_1992, pospischil_minimal_2008,Kispersky2012, golowasch_failure_2002, barreiro_-current_2012}, however other properties of ionic currents impact neuronal firing as well.
%In addition, cell-type specific effects on firing are possible. For instance, the R1648H mutation in \textit{SCN1A} increases firing in inhibitory interneurons but not pyramidal neurons \citep{Hedrich14874}. In extreme cases, a mutation can have opposite effects on different neuron types. For example, the homologous mutation R1627H in \textit{SCN8A} is associated which increased firing in interneurons, but decreases pyramidal neuron excitability \citep{makinson_scn1a_2016}.
%For instance, the R1648H mutation in \textit{SCN1A} increases firing in inhibitory interneurons but not pyramidal neurons \citep{Hedrich14874}. In extreme cases, a mutation can have opposite effects on different neuron types. For example, the homologous mutation R1627H in \textit{SCN8A} is associated which increased firing in interneurons, but decreases pyramidal neuron excitability \citep{makinson_scn1a_2016}.
Despite this evidence of cell-type specific effects of ion channel mutations on firing, the dependence of firing outcomes of ion channel mutations is generally not known. Cell-type specificity is likely vital for successful precision medicine treatment approaches. For example, Dravet syndrome was identified as the consquence of LOF mutations in \textit{SCN1A} \citep{Claes2001,Fujiwara2003,Ohmori2002}, however limited success in treatment of Dravet syndrome persisted \citep{Claes2001,Oguni2001}. \textcolor{red}{until it became evident that inhibitory interneurons and not pyramidal neurons had altered excitability as a result of LOF \textit{SCN1A} mutations \citep{Yu2006, Colasante2020}}. \textit{Once it became evident that inhibitory interneurons and not pyramidal neurons had altered excitability as a result of LOF \textit{SCN1A} mutations \citep{Yu2006}, alternative approaches based on this understanding began to show promise \citep{Colasante2020}.}
Despite this evidence of cell-type specific effects of ion channel mutations on firing, the dependence of firing outcomes in ion channel mutations on cell-type is generally not known. Cell-type specificity is likely vital for successful precision medicine treatment approaches. For example, Dravet syndrome was identified as the consquence of LOF mutations in \textit{SCN1A} \citep{Claes2001,Fujiwara2003,Ohmori2002}, however limited success in treatment of Dravet syndrome persisted \citep{Claes2001,Oguni2001}. \textcolor{red}{until it became evident that inhibitory interneurons and not pyramidal neurons had altered excitability as a result of LOF \textit{SCN1A} mutations \citep{Yu2006, Colasante2020}}. \textit{Once it became evident that inhibitory interneurons and not pyramidal neurons had altered excitability as a result of LOF \textit{SCN1A} mutations \citep{Yu2006}, alternative approaches based on this understanding began to show promise \citep{Colasante2020}.}
%Once it became evident that only inhibitory interneurons and not pyramidal neurons had altered excitability as a result of LOF \textit{SCN1A} mutations \citep{Yu2006} alternative approaches, based on this understanding such as gene therapy, began to show promise \citep{Colasante2020}.
Due to the high clinical relevance of understanding cell-type dependent effects of channelopathies, computational modelling approaches are used to assess the impacts of altered ionic current properties on firing behavior, bridging the gap between changes in the biophysical properties induced by mutations, firing and clinical symptoms. Conductance-based neuronal models enable insight into the effects of ion channel mutations with specific effects of the resulting ionic current as well as enabling \textit{in silico} assessment of the relative effects of changes in biophysical properties of ionic currents on neuronal firing. Furthermore, modelling approaches enable predictions of the effects of a specific mutation and drug induced biophysical property changes \citep{Layer2021,Liu2019,johannesen_genotype-phenotype_2021, lauxmann_therapeutic_2021}.
@ -449,6 +449,7 @@ With this study we suggest that cell-type specific effects are vital to a full u
\newpage
\setcounter{figure}{0}
\section*{Figures}
% \textit{Figures must be numbered independently of tables and multimedia and cited in the manuscript. Do not duplicate data by presenting it both in the text and in a figure.
% A title should be part of the legend and not lettered onto the figure. A legend must be included in the manuscript document after the reference list, and should include enough detail to be intelligible without reference to the text. Specific individuals’ contributions to data acquisition, analysis, or other responsibility resulting in a figure may be included at the end of each legend. Please use the heading “Figure Contributions” and state each contribution with the author’s full name.
@ -459,18 +460,16 @@ With this study we suggest that cell-type specific effects are vital to a full u
% Remove top and right borderlines that to not contain measuring metrics from all graph/histogram figure panels (i.e., do not box the panels in). Do not include any two-bar graphs/histograms; instead state those values in the text.
% All illustrations documenting results must include a bar to indicate the scale. All labels used in a figure should be explained in the legend. The migration of protein molecular weight size markers or nucleic acid size markers must be indicated and labeled appropriately (e.g., “kD”, “nt”, “bp”) on all figure panels showing gel electrophoresis.}
\setcounter{figure}{0}
\begin{figure}[tp]
\centering
\includegraphics[width=\linewidth]{Figures/diversity_in_firing.pdf}
\includegraphics[width=0.9\linewidth]{Figures/diversity_in_firing.pdf}
\linespread{1.}\selectfont
\caption[]{Diversity in Neuronal Model Firing. Spike trains (left), frequency-current (fI) curves (right) for Cb stellate (A), RS inhibitory (B), FS (C), RS pyramidal (D), RS inhibitory +\Kv (E), Cb stellate +\Kv (F), FS +\Kv (G), RS pyramidal +\Kv (H), STN +\Kv (I), Cb stellate \(\Delta\)\Kv (J), STN \(\Delta\)\Kv (K), and STN (L) neuron models. Models are sorted qualitatively based on their fI curves. Black markers on the fI curves indicate the current step at which the spike train occurs. The green marker indicates the current at which firing begins in response to an ascending current ramp, whereas the red marker indicates the current at which firing ceases in response to a descending current ramp (see \Cref{fig:ramp_firing}).}
\label{fig:diversity_in_firing}
\end{figure}
\begin{figure}[tp]
\centering
\includegraphics[width=0.5\linewidth]{Figures/firing_characterization_arrows.pdf}
@ -582,6 +581,6 @@ Changes in firing as characterized by \(\Delta\)AUC and \(\Delta\)rheobase occup
% \textit{A legend for the code file, labeled as “Extended Data 1,” should be at the end of the manuscript.\\}
% The code files must be packaged into a single ZIP file, uploaded to the submission system as a “Multimedia/Extended Data” file type.}
\captionof{Extended Data}{Code in zip file. Description needs to be added once code is ready.}
\captionof{Extended Data}{Python code for simulations and analysis in zip file. Simulation code for each model, the sensitvity analysis of each model, the simulation of \textit{KCNA1} mutations in each model, and all analysis are provided herein.}
\end{document}