slightly better version of introduction

manuscript.tex

@@ -114,9 +114,10 @@ Voltage-gated ion channels are vital in determining neuronal excitability, actio
 
 Research on the effect of these altered currents on neuronal firing is important for understanding the disease and finding possible mediactions. There are a lot of widely accepted experimtental approaches. Transfection of heterologous expression systems without endogenous currents reveals changes in ion current kinetics \textcolor{red}{(cite some stuff)}. Simulations of these effects can predict their effect on neuronal firing \textcolor{red}{(cite some stuff)}. Or the influence on firing behaviour can be directly measured in transfected primary neuronal cultures \textcolor{red}{(cite some stuff)} or brain slice recrodings of mouse lines \textcolor{red}{(cite some stuff)}. 
 
-However, \textcolor{red}{since experimental ressources are limited,} the effect on the firing behaviour of different neuron types is often unclear \textcolor{red}{(and always incomplete)}. Different neuron types have different ion current compositions and therefore should react differently to changes in one current. In most cases, the effect size should depend on the expression level of the affected current \textcolor{red}{(cite some stuff, cite NikoPaper)}. \textcolor{red}{Qualitative changes with expression level can also be assumed (probably Yuanyuan 2019, \citep{rutecki_neuronal_1992, pospischil_minimal_2008,Kispersky2012, golowasch_failure_2002, barreiro_-current_2012, Noebels2017})}. Two neuron types can even be affected in completly different ways. The R1629H mutation in \textcolor{red}{SCN8A} for example causes less firing in pyramidal neurons, while affected interneurons have more action potentials.
+However, \textcolor{red}{since experimental ressources are limited,} the effect on the firing behaviour of different neuron types is often unclear \textcolor{red}{(and always incomplete)}. Different neuron types have different ion current compositions and therefore should react differently to changes in one current. In the simpler cases, the respective behaviour changes should mostly depend on the expression level of the affected current and scale with it \textcolor{red}{(cite some stuff, cite NikoPaper)}. 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}. 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)}. 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?)}.
+
+In this study we want to get an insight into how changes in ion current kinetics change firing behaviour dependent on neuron type. We will simulate a repertoire of different neuronal models and compare those changes.
 
-In this study, we simulate a repertoire of different neuron models to research the comparability of influence of changes in ion current properties on neuronal firing behaviour.
 
 %Neuronal 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 disturb 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 \citep{bernard_channelopathies_2008, carbone_ion_2020}. The effects of these mutations are frequently presumed \cite{Balestrini1044} or determined at a biophysical level, however assessment of the impact of mutations on neuronal firing and excitability is more difficult. Experimentally, cell culture transfection does not replicate the exact interplay of endogenous currents nor does it take into account the complexity of the nervous system including factors such as expression patterns, intracellular regulation and modulation of ion channels as well as network effects \cite{Balestrini1044, Noebels2017}. Transfected currents are characterized in isolation and the role of these isolated currents in the context of other currents in a neuron cannot be definitively inferred \cite{Dunlop2008, Noebels2017}. Additionally, transfected currents are not expressed in the presence of physiologically present auxillary proteins and are even transfected in cells of different species. Furthermore, culture conditions can shape ion channel expression \citep{ponce_expression_2018}. 
 % Complex interactions between different cell types and circuit level effects \textit{in vivo} are neglected in transfected cell culture.