Re-wrote abstract

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@@ -158,9 +158,28 @@ Nils A. Koch\textsuperscript{1,2}, Lukas Sonnenberg\textsuperscript{1,2}, Ulrike
 \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
 
-\section*{Abstract (250 Words Maximum - Currently)}
+\section*{Abstract (250 Words Maximum - Currently 252)}
 %\textit{It should provide a concise summary of the objectives, methodology (including the species and sex studied), key results, and major conclusions of the study.}
 
+Clinically relevant mutations to voltage-gated  ion channels, called channelopathies, result in altered ion channel function and ionic current properties.The effects of ion channel mutations on ionic current properties is routinely assessed and characterized as loss of function (LOF) or gain of function (GOF). Although personalized medicine approaches based on these assessments are emerging for channelopathy treatment, they are likely limited by the lack of detailed knowledge on the effects of channelopathies on firing across the brain. As experimental investigation of the effects of channelopathies on neuronal firing are difficult and impractical, direct translation of current level LOF/GOF to effects on neuronal firing level is tempting. Are these heuristic translation approaches sufficient given that cell-type specific effects of ion channel mutations have been reported? To investigate the impact of neuronal cell type on the firing outcome of ion channel mutations, computational modelling with a diverse collection of neuronal models is used here. In particular, systematic simulation and evaluation of the effects of changes in ion current properties on firing properties in different neuronal types as well as for mutations in the \textit{KCNA1} gene encoding the \Kv potassium channel subtype associated with episodic ataxia type~1 (EA1) revealed that the outcome of a given change in ion channel properties, such as by a mutation, 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.
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+%Clinically relevant genetic alterations to ion channels, or channelopathies, are often categorized as gain or loss of function at the ionic current level. This characterization is often instinctively extended to the level of neuronal firing to aid in personalized medicine approaches. However, the direct translation from gain or loss of function at the current level to firing level effects is not directly possible without consideration of the context in which the mutated ion channel operates. 
+%By using a collection of established neuronal models, cell-type dependent diversity in the effects of altered ion current properties on firing are demonstrated. The importance of cell-type dependent in the outcome of channelopathies on firing is illustrated by simulation of the effect of episodic ataxia type 1 associated \textit{KCNA1} mutations on firing across the diverse collection of neuronal models. In the investigation of channelopathies and translation into personalized medicine approaches, cell-type dependent effects of channelopathies must be considered to understand the effects of altered channel function at the level of neuronal firing.
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+% intro: channelopathies and personalized med
+%intro trans: difficult to go for LOF/GOF to firing
+%use simulation to investigate the role of cell-type on firing outcomes of changes in ion currents generally and in KCNA1 EA1 assoc mutation
+%conclusions: Cell-type dependent effects of channelopathies must be considered and will likely improve personalized medicine approaches
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 %Neuronal excitability is shaped by kinetics of ion channels and disruption in ion channel properties caused by mutations can result in neurological disorders called channelopathies. Often, mutations within one gene are associated with a specific channelopathy. The effects of these mutations  on channel function, i.e. the ionic current conducted by the affected ion channels, are generally characterized using heterologous expression systems. Nevertheless, the impact of such mutations on neuronal firing is essential not only for determining brain function, but also for selecting personalized treatment options for the affected patient. The effect of ion channel mutations on firing in different cell types has been mostly neglect and it is unclear whether the effect of a given mutation on firing can simply be inferred from the effects identified at the current level. Here we use a diverse collection of computational neuronal models to determine that ion channel mutation effects at the current level cannot be indiscriminantly used to infer firing effects without consideration of cell-type. In particular, systematic simulation and evaluation of the effects of changes in ion current properties on firing properties in different neuronal types as well as for mutations in the \textit{KCNA1} gene encoding the \Kv potassium channel subtype associated with episodic ataxia type~1 (EA1) was performed. The effects of changes in ion current properties generally and due to mutations in the \Kv channel subtype on the firing of a neuron depends on the ionic current environment, or the neuronal cell type, in which such a change occurs in. Thus, while characterization of ion channel mutations as loss or gain of function is useful at the level of the ionic current, this characterization should not be extended to the level of neuronal excitability as the effects of ion channel mutations on the firing of a cell is dependent on the cell type and the composition of different ion channels and subunits therein. For increased efficiency and efficacy of personalized medicine approaches in channelopathies, the effects of ion channel mutations must be examined in the context of the appropriate cell types in which these mutations occur.
 %%Using a diverse collection of computational neuronal models, the effects of changes in ion current properties on firing properties of different neuronal types were simulated systematically and for mutations in the \textit{KCNA1} gene encoding the \Kv potassium channel subtype associated with episodic ataxia type~1 (EA1). The effects of changes in ion current properties or changes due to mutations in the \Kv channel subtype on the firing of a neuron depends on the ionic current environment, or the neuronal cell type, in which such a change occurs in. Characterization of ion channel mutations as loss or gain of function is useful at the level of the ionic current. However, the effects of mutations causing channelopathies on the firing of a cell is dependent on the cell type and thus on the composition of different ion channels and subunits. To further the efficacy of personalized medicine in channelopathies, the effects of ion channel mutations must be examined in the context of the appropriate cell types in which these mutations occur.