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@ -94,73 +94,70 @@
\vspace{-1em}
\date{}
\section*{Titlepage for eNeuro - will be put into Word file provided for submission}
\subsection{Manuscript Title (50 word maximum)}
Loss or Gain of Function? Effects of Ion Channel Mutations on Neuronal Firing Depend on the Cell Type
\subsection{Abbreviated Title (50 character maximum)}
Effects of Ion Channel Mutation Depend on Cell Type
\subsection{List all Author Names and Affiliations in order as they would appear in the published article}
Nils A. Koch\textsuperscript{1,2}, Lukas Sonnenberg\textsuperscript{1,2}, Ulrike B.S. Hedrich\textsuperscript{3}, Stephan Lauxmann\textsuperscript{1,3}, Jan Benda\textsuperscript{1,2}
\textsuperscript{1}Institute for Neurobiology, University of Tuebingen, 72072 Tuebingen, Germany\\
\textsuperscript{2}Bernstein Center for Computational Neuroscience Tuebingen, 72076 Tuebingen, Germany\\
\textsuperscript{3}Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tuebingen, 72076 Tuebingen, Germany\\
\subsection{Author Contributions - Each author must be identified with at least one of the following: Designed research, Performed research, Contributed unpublished reagents/ analytic tools, Analyzed data, Wrote the paper.}
\notenk{Adjust as you deem appropriate}\\
NK, LS, UBSH, SL, JB Designed Research;
NK Performed research;
NK, LS Analyzed data;
NK, LS, UBSH, SL, JB Wrote the paper
\subsection{Correspondence should be addressed to (include email address)}
\
Jan Benda jan.benda@uni-tuebingen.de
\subsection{Number of Figures}
5
\subsection{Number of Tables}
3
\subsection{Number of Multimedia}
0
\subsection{Number of words for Abstract}
205
\subsection{Number of Words for Significance Statement}
119
\subsection{Number of words for Discussion}
2353
\subsection{Acknowledgements}
\subsection{Conflict of Interest}
Authors report no conflict of interest.
\\\textbf{A.} The authors declare no competing financial interests.
\subsection{Funding sources}
\notejb{SmartStart}
This work was supported by the German Research Foundation in the Frame of the Research Unit FOR-2715 (DFG, grants Le1030/15-1/2 and HE 8155/1-2) and the Network for Rare Ion Channel Disorders Treat-ION of the Federal Ministry for Education and Research (BMBF, grants 01GM1907A and 01GM2210A). SL was supported with an Otfrid-Foerster stipend from the German Society for Epileptology (DGfE).
\section*{Publishing Topic}
\begin{enumerate}
\item Development;
\item \textbf{Neuronal Excitability};
\item Sensory and Motor Systems;
\item Integrative Systems;
\item Cognition and Behavior;
\item Novel Tools and Methods;
\item Disorders of the Nervous System;
\item or History, Teaching, and Public Awareness.
\end{enumerate}
\section*{Other issue for Submission}
\textit{Authors will be asked to choose one or two preferred Reviewing Editor(s) in order of preference. Editor assignments will be made based on the expertise of the editors, load, and scheduling. Authors may also exclude reviewing editors from handling their manuscripts.}
\url{https://www.eneuro.org/content/editorial-board#reviewing_editors}\\
\textit{Authors may optionally identify up to 5 reviewers who are well qualified to referee the work and who would not have a conflict of interest. Authors should provide the name, address, and email for each potential referee}
\newpage{}
%\section*{Titlepage for eNeuro - will be put into Word file provided for submission}
%\subsection{Manuscript Title (50 word maximum)}
%Loss or Gain of Function? Effects of Ion Channel Mutations on Neuronal Firing Depend on the Cell Type
%
%\subsection{Abbreviated Title (50 character maximum)}
%Effects of Ion Channel Mutation Depend on Cell Type
%
%\subsection{List all Author Names and Affiliations in order as they would appear in the published article}
%Nils A. Koch\textsuperscript{1,2}, Lukas Sonnenberg\textsuperscript{1,2}, Ulrike B.S. Hedrich\textsuperscript{3}, Stephan Lauxmann\textsuperscript{1,3}, Jan Benda\textsuperscript{1,2}
%
%\textsuperscript{1}Institute for Neurobiology, University of Tuebingen, 72072 Tuebingen, Germany\\
%\textsuperscript{2}Bernstein Center for Computational Neuroscience Tuebingen, 72076 Tuebingen, Germany\\
%\textsuperscript{3}Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tuebingen, 72076 Tuebingen, Germany\\
%
%\subsection{Author Contributions - Each author must be identified with at least one of the following: Designed research, Performed research, Contributed unpublished reagents/ analytic tools, Analyzed data, Wrote the paper.}
%\notenk{Adjust as you deem appropriate}\\
%NK, LS, UBSH, SL, JB Designed Research;
%NK Performed research;
%NK, LS Analyzed data;
%NK, LS, UBSH, SL, JB Wrote the paper
%
%\subsection{Correspondence should be addressed to (include email address)}
%\
%Jan Benda jan.benda@uni-tuebingen.de
%\subsection{Number of Figures}
% 5
%\subsection{Number of Tables}
%3
%\subsection{Number of Multimedia}
%0
%\subsection{Number of words for Abstract}
%205
%
%\subsection{Number of Words for Significance Statement}
%119
%\subsection{Number of words for Discussion}
%2353
%\subsection{Acknowledgements}
%
%\subsection{Conflict of Interest}
%Authors report no conflict of interest.
%\\\textbf{A.} The authors declare no competing financial interests.
%\subsection{Funding sources}
%\notejb{SmartStart}
%This work was supported by the German Research Foundation in the Frame of the Research Unit FOR-2715 (DFG, grants Le1030/15-1/2 and HE 8155/1-2) and the Network for Rare Ion Channel Disorders Treat-ION of the Federal Ministry for Education and Research (BMBF, grants 01GM1907A and 01GM2210A). SL was supported with an Otfrid-Foerster stipend from the German Society for Epileptology (DGfE).
%
%\section*{Publishing Topic}
%\begin{enumerate}
% \item Development;
% \item \textbf{Neuronal Excitability};
% \item Sensory and Motor Systems;
% \item Integrative Systems;
% \item Cognition and Behavior;
% \item Novel Tools and Methods;
% \item Disorders of the Nervous System;
% \item or History, Teaching, and Public Awareness.
%\end{enumerate}
%
%\section*{Other issue for Submission}
%\textit{Authors will be asked to choose one or two preferred Reviewing Editor(s) in order of preference. Editor assignments will be made based on the expertise of the editors, load, and scheduling. Authors may also exclude reviewing editors from handling their manuscripts.}
%\url{https://www.eneuro.org/content/editorial-board#reviewing_editors}\\
%\textit{Authors may optionally identify up to 5 reviewers who are well qualified to referee the work and who would not have a conflict of interest. Authors should provide the name, address, and email for each potential referee}
%
%\newpage{}
\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
@ -182,13 +179,13 @@ Nils A. Koch\textsuperscript{1,2}, Lukas Sonnenberg\textsuperscript{1,2}, Ulrike
Clinically relevant mutations to voltage-gated ion channels, called channelopathies, alter ion channel function, properties of ionic current and neuronal firing. The effects of ion channel mutations are routinely assessed and characterized as loss of function (LOF) or gain of function (GOF) at the level of ionic currents. Emerging personalized medicine approaches based on LOF/GOF characterization have limited therapeutic success. Potential reasons are that the translation from this binary characterization to neuronal firing especially when considering different neuronal cell types is currently not well understood. Here we investigate the impact of neuronal cell type on the firing outcome of ion channel mutations with simulations of a diverse collection of neuron models. We systematically analyzed the effects of changes in ion current properties on firing in different neuronal types. Additionally, we simulated the effects of mutations in the \textit{KCNA1} gene encoding the \Kv potassium channel subtype associated with episodic ataxia type~1 (EA1). These simulations revealed that the outcome of a given change in ion channel properties on neuronal excitability is cell-type dependent. As a result, cell-type specific effects are vital to a full understanding of the effects of channelopathies on neuronal excitability and present an opportunity to further the efficacy and precision of personalized medicine approaches.
\section*{Significance Statement (120 Words Maximum - Currently 119 )}
\section*{Significance Statement}
%\textit{The Significance Statement should provide a clear explanation of the importance and relevance of the research in a manner accessible to researchers without specialist knowledge in the field and informed lay readers. The Significance Statement will appear within the paper below the abstract.}
Although the genetic nature of ion channel mutations as well as their effects on the biophysical properties of an ion channel are routinely assessed experimentally, determination of their role in altering neuronal firing is more difficult. In particular, cell-type dependency of ion channel mutations on firing has been observed experimentally, and should be accounted for. In this context, computational modelling bridges this gap and demonstrates that the cell type in which a mutation occurs is an important determinant in the effects of neuronal firing. As a result, classification of ion channel mutations as loss or gain of function is useful to describe the ionic current but should not be blindly extend to classification at the level of neuronal firing.
\section*{Introduction (750 Words Maximum - Currently 708)}
\section*{Introduction}
%\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 neuronal excitability \citep{bernard_channelopathies_2008, carbone_ion_2020, rutecki_neuronal_1992, pospischil_minimal_2008}. 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 increase in the discovery of clinically relevant ion channel 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}.
@ -285,7 +282,7 @@ Although changes in half maximal potential \(V_{1/2}\) and slope factor \(k\) ge
\subsection*{\textit{KCNA1} Mutations}
Mutations in \textit{KCNA1} are associated with episodic ataxia type~1 (EA1) and have been characterized biophysically (as reviewed by \citet{lauxmann_therapeutic_2021}). Here they were used as a test case in the effects of various ionic current environments on neuronal firing and on the outcomes of channelopathies. The changes in AUC and rheobase from wild type values for reported EA1 associated \textit{KCNA1} mutations were heterogeneous across models containing \Kv, but generally showed decreases in rheobase (\Cref{fig:simulation_model_comparision}A--I). Pairwise non-parametric Kendall \(\tau\) rank correlations between the simulated effects of these \Kv mutations on rheobase were highly correlated across models (\Cref{fig:simulation_model_comparision}J) indicating that EA1 associated \textit{KCNA1} mutations generally decrease rheobase across diverse cell-types. However, the effects of the \Kv mutations on AUC were more heterogenous as reflected by both weak and strong positive and negative pairwise correlations between models (\Cref{fig:simulation_model_comparision}K), suggesting that the effects of ion-channel variant on super-threshold neuronal firing depend both quantitatively and qualitatively on the specific composition of ionic currents in a given neuron.
\section*{Discussion (3000 Words Maximum - Currently 2353)}
\section*{Discussion}
% \textit{The discussion section should include a brief statement of the principal findings, a discussion of the validity of the observations, a discussion of the findings in light of other published work dealing with the same or closely related subjects, and a statement of the possible significance of the work. Extensive discussion of the literature is discouraged.}
To compare the effects of ion channel mutations on neuronal firing of different neuron types, a diverse set of conductance-based models was used and the effect of changes in individual channel properties across conductance-based neuronal models. Additionally, the effects of episodic ataxia type~1 associated (EA1) \textit{KCNA1} mutations were simulated. Changes to single ionic current properties, as well as known EA1 associated \textit{KCNA1} mutations showed consistent effects on the rheobase across cell types, whereas the effects on AUC of the steady-state fI-curve depended on the cell type. Our results demonstrate that loss of function (LOF) and gain of function (GOF) on the biophysical level cannot be uniquely transferred to the level of neuronal firing. Thus, the effects caused by different mutations depend on the properties of the other ion channels expressed in a cell and are therefore depend on the channel ensemble of a specific cell type.