added short LOF-GOF intro to introduction and other small changes

manuscript.tex

@@ -121,7 +121,9 @@ Ion channels determine neuronal excitability and mutations that alter ion channe
 
 Voltage-gated ion channels are vital in determining neuronal excitability, action potential generation and firing patterns \citep{bernard_channelopathies_2008, carbone_ion_2020}. In particular, the properties and combinations of ion channels and their resulting currents determine the firing properties of the neuron \citep{rutecki_neuronal_1992, pospischil_minimal_2008}. However, ion channel function can be disturbed, resulting in altered ionic current properties and altered neuronal firing behaviour \citep{carbone_ion_2020}. Ion channel mutations are a common cause of such channelopathies and are often associated with hereditary clinical disorders including ataxias, epilepsies, pain disorders, dyskinesias, intellectual disabilities, myotonias, and periodic paralyses among others  \citep{bernard_channelopathies_2008, carbone_ion_2020}.
 
-Although the effects of channelopathies on ionic-current kinetics are frequently assessed by transfection of heterologous expression systems without endogenous currents  \citep{Balestrini1044, Noebels2017, Dunlop2008} \textcolor{red}{(cite more stuff?)}, the effect of these changes on neuronal firing is important for understanding the pathophysiology of these disorders and for identification of potential therapeutic targets \textcolor{red}{(cite some stuff)}. Experimentally, the effects of channelopathies on neuronal firing can be assessed using primary neuronal cultures  \citep{Scalmani2006, Smith2018, Liu2019} \textcolor{red}{(cite more stuff?)} or \textit{in vitro} recordings from transgenic mouse lines \textcolor{red}{(cite some stuff)}.
+The effects of channelopathies on ionic-current kinetics are frequently assessed by transfection of heterologous expression systems without endogenous currents  \citep{Balestrini1044, Noebels2017, Dunlop2008} \textcolor{red}{(cite more stuff?)} and are categorized into loss-of-function (LOF) or gain-of-function (GOF) effects. With these caterogies it is possible to estimate changes in neuronal firing. These estimates are important for understanding the pathophysiology of these disorders and for identification of potential therapeutic targets \textcolor{red}{(cite some stuff)}. Experimentally, the effects of channelopathies on neuronal firing can also be assessed using primary neuronal cultures \citep{Scalmani2006, Smith2018, Liu2019} \textcolor{red}{(cite more stuff?)} or \textit{in vitro} recordings from transgenic mouse lines \textcolor{red}{(cite some stuff)}.
+
+\notels{LOF and GOF are usually not explained in detail, should we still do this here or is it ok to just mention them?}
 
 %However the effect of a given channelopathy on different neuronal types across the brain is often unclear and not feasible to experimentally obtain. This is especially true when large numbers of distinct mutations are present and personalized medicine approaches are desired.
 
@@ -129,11 +131,9 @@ Although the effects of channelopathies on ionic-current kinetics are frequently
 
 
 %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 differ in their composition of ionic currents \citep{yao2021taxonomy} \textcolor{red}{(cite Berens)} and therefore likely respond differently to changes in the properties of one ionic 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 \citep{Layer2021} \textcolor{red}{(cite other Papers?)}, however if a gating property is altered substantially this can have complex consequences.
+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 differ in their composition of ionic currents \citep{yao2021taxonomy} \textcolor{red}{(cite Berens)} and therefore likely respond differently to changes in the properties of one ionic current.  The expression level of an affected gene can correlate with firing behaviour in the simplest case \citep{Layer2021} \textcolor{red}{(cite other Papers?)}, however if a gating property is altered substantially this can have complex consequences.
 
-For instance, altering relative amplitudes of ionic currents 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 properties of ionic currents 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?)}.  \notenk{Lukas I'm not sure which other paper you are referencing}
+For instance, altering relative amplitudes of ionic currents 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 properties of ionic currents 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,makinson2016scn1a}
 
 %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

@@ -1404,5 +1404,19 @@ SIGNIFICANCE: Bromide is most effective and is a well-tolerated drug among DS pa
 }
 
 
+@article{makinson2016scn1a,
+  title={An Scn1a epilepsy mutation in Scn8a alters seizure susceptibility and behavior},
+  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},
+  volume={275},
+  pages={46--58},
+  year={2016},
+  publisher={Elsevier},
+  language = {en},
+  url={https://doi.org/10.1016/j.expneurol.2015.09.008},
+  doi={10.1016/j.expneurol.2015.09.008}
+}
+
+
 
 @Comment{jabref-meta: databaseType:bibtex;}