Merge branch 'master' of https://whale.am28.uni-tuebingen.de/git/nkoch/model_mutations_2022

manuscript.tex

@@ -160,7 +160,7 @@ Ion channels determine neuronal excitability and mutations that alter ion channe
 \par\null
 
 
-\notejb{LOF or LoF? GOF or GoF?}
+\notejb{LOF or LoF? GOF or GoF?} \notels{LOF and GoF!!! (I think it is usually all big letters, not 100\% sure though)}
 
 \section*{Introduction (750 Words Maximum  - Currently 592)} 
 %\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.}
@@ -168,7 +168,7 @@ 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}.
 
 \notenk{Are there any obvious citations missing from the following section?}
-The effects of channelopathies on ionic current kinetics are frequently assessed by transfection of heterologous expression systems without endogenous currents  \citep{Balestrini1044, Noebels2017, Dunlop2008}, and are frequently classified as either a loss of function (LOF) or a gain of function (GOF) with respect to the ionic current \citep{Musto2020, Kullmann2002, Waxman2011}. \notenk{Do you think we need to discuss LOF and GOF more than this?} However, the effect of these changes on neuronal firing is important for understanding the pathophysiology of these disorders and for identification of potential therapeutic targets \citep{Orsini2018, Yang2018}. 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 transgenic mouse lines \citep{Mantegazza2019, Xie2010,Lory2020, Habib2015,  Hedrich2019}.
+The effects of channelopathies on ionic current kinetics are frequently assessed by transfection of heterologous expression systems without endogenous currents  \citep{Balestrini1044, Noebels2017, Dunlop2008}, and are frequently classified as either a loss of function (LOF) or a gain of function (GOF) with respect to \textcolor{green}{changes in }the \textcolor{green}{amount of} ionic current \citep{Musto2020, Kullmann2002, Waxman2011}. \notenk{Do you think we need to discuss LOF and GOF more than this?} \notels{LOF and GOF are usually not explained in detail, I would think it's fine}  These classes can be used to make rough estimates of the effects on neuronal firing \textcolor{red}{(papers?)}, which is important for understanding the pathophysiology of these disorders and for identification of potential therapeutic targets \citep{Orsini2018, Yang2018}. 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 transgenic mouse lines \citep{Mantegazza2019, Xie2010,Lory2020, Habib2015,  Hedrich2019}.
 
 %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.
 
@@ -180,7 +180,7 @@ However the effect of a given channelopathy on different neuronal types across t
 % \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?)} \notenk{Not sure if Lukas had some in mind}, 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

@@ -8,7 +8,7 @@
   number   = {7879},
   pages    = {86--102},
   volume   = {598},
-  abstract = {Here we report the generation of a multimodal cell census and atlas of the mammalian primary motor cortex as the initial product of the BRAIN Initiative Cell Census Network (BICCN). This was achieved by coordinated large-scale analyses of single-cell transcriptomes, chromatin accessibility, DNA methylomes, spatially resolved single-cell transcriptomes, morphological and electrophysiological properties and cellular resolution input–output mapping, integrated through cross-modal computational analysis. Our results advance the collective knowledge and understanding of brain cell-type organization–. First, our study reveals a unified molecular genetic landscape of cortical cell types that integrates their transcriptome, open chromatin and DNA methylation maps. Second, cross-species analysis achieves a consensus taxonomy of transcriptomic types and their hierarchical organization that is conserved from mouse to marmoset and human. Third, in situ single-cell transcriptomics provides a spatially resolved cell-type atlas of the motor cortex. Fourth, cross-modal analysis provides compelling evidence for the transcriptomic, epigenomic and gene regulatory basis of neuronal phenotypes such as their physiological and anatomical properties, demonstrating the biological validity and genomic underpinning of neuron types. We further present an extensive genetic toolset for targeting glutamatergic neuron types towards linking their molecular and developmental identity to their circuit function. Together, our results establish a unifying and mechanistic framework of neuronal cell-type organization that integrates multi-layered molecular genetic and spatial information with multi-faceted phenotypic properties., The BRAIN Initiative Cell Census Network has constructed a multimodal cell census and atlas of the mammalian primary motor cortex in a landmark effort towards understanding brain cell-type diversity, neural circuit organization and brain function.},
+  abstract = {Here we report the generation of a multimodal cell census and atlas of the mammalian primary motor cortex as the initial product of the BRAIN Initiative Cell Census Network (BICCN). This was achieved by coordinated large-scale analyses of single-cell transcriptomes, chromatin accessibility, DNA methylomes, spatially resolved single-cell transcriptomes, morphological and electrophysiological properties and cellular resolution input–output mapping, integrated through cross-modal computational analysis. Our results advance the collective knowledge and understanding of brain cell-type organization–. First, our study reveals a unified molecular genetic landscape of cortical cell types that integrates their transcriptome, open chromatin and DNA methylation maps. Second, cross-species analysis achieves a consensus taxonomy of transcriptomic types and their hierarchical organization that is conserved from mouse to marmoset and human. Third, in situ single-cell transcriptomics provides a spatially resolved cell-type atlas of the motor cortex. Fourth, cross-modal analysis provides compelling evidence for the transcriptomic, epigenomic and gene regulatory basis of neuronal phenotypes such as their physiological and anatomical properties, demonstrating the biological validity and genomic underpinning of neuron types. We further present an extensive genetic toolset for targeting glutamatergic neuron types towards linking their molecular and developmental identity to their circuit function. Together, our results establish a unifying and mechanistic framework of neuronal cell-type organization that integrates multi-layered molecular genetic and spatial information with multi-faceted phenotypic properties., The BRAIN Initiative Cell Census Network has constructed a multimodal cell census and atlas of the mammalian primary motor cortex in a landmark effort towards understanding brain cell-type diversity, neural circuit organization and brain function.},
   doi      = {10.1038/s41586-021-03950-0},
   file     = {PubMed Central Link:https\://www.ncbi.nlm.nih.gov/pmc/articles/PMC8494634/:text/html},
   pmcid    = {PMC8494634},
@@ -1619,6 +1619,20 @@ SIGNIFICANCE: Bromide is most effective and is a well-tolerated drug among DS pa
   urldate  = {2022-05-06},
 }
 
+
+@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}
+}
+
  
 @Article{Waxman2011,
   author    = {Waxman, Stephen G.},
@@ -1641,4 +1655,5 @@ SIGNIFICANCE: Bromide is most effective and is a well-tolerated drug among DS pa
   urldate   = {2022-05-06},
 }
 
+
 @Comment{jabref-meta: databaseType:bibtex;}