diff --git a/manuscript.tex b/manuscript.tex index fea56c7..eb79903 100644 --- a/manuscript.tex +++ b/manuscript.tex @@ -199,7 +199,10 @@ Although the genetic nature of ion channel mutations as well as their effects on \section*{Introduction (750 Words Maximum - Currently 704)} %\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 increasing number 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}. Ongoing efforts of many research groups have contributed to the current understanding of underlying disease mechanism in channelopathies, however a complex pathophysiological landscape has emerged for many channelopathies and is likely a reason for limited therapeutic success with standard care. +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}. +\textit{In recent years, next generation sequencing has led to an increasing number 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}.} +\textcolor{red}{In recent years, next generation sequencing has led to an increase in discoveries 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}.} +Ongoing efforts of many research groups have contributed to the current understanding of underlying disease mechanism in channelopathies, however a complex pathophysiological landscape has emerged for many channelopathies and is likely a reason for limited therapeutic success with standard care. Ion channel variants are frequently classified in heterologous expression systems as either a loss of function (LOF) or a gain of function (GOF) in the respective ionic current \citep{Musto2020, Kullmann2002, Waxman2011, Kim2021}. This LOF/GOF classification is often directly used to predict the effects on neuronal firing \citep{Niday2018, Wei2017, Wolff2017,Masnada2017}, which in turn is important for understanding the pathophysiology of these disorders and for identification of potential therapeutic targets \citep{Orsini2018, Yang2018, Colasante2020, Yu2006}. Experimentally, the effects of channelopathies on neuronal firing are assessed using primary neuronal cultures \citep{Scalmani2006, Smith2018, Liu2019} or \textit{in vitro} recordings from slices of transgenic mouse lines \citep{Mantegazza2019, Xie2010,Lory2020, Habib2015, Hedrich14874} but are restricted to limited number of neuronal types. Different neuron types differ in their composition of ionic currents \citep{yao2021taxonomy, Cadwell2016, BICCN2021, Scala2021} and therefore likely respond differently to changes in the properties of a single ionic current. Expression level of an affected gene \citep{Layer2021} and relative amplitudes of ionic currents \citep{rutecki_neuronal_1992, pospischil_minimal_2008,Kispersky2012, golowasch_failure_2002, barreiro_-current_2012} indeed dramatically influence the firing behavior and dynamics of neurons. Mutations in different sodium channel genes have been experimentally shown to affect firing in a cell-type specific manner based on differences in expression levels of the affected gene \citep{Layer2021}, but also on other cell-type specific mechanisms \citep{Hedrich14874, makinson_scn1a_2016}. diff --git a/ref.bib b/ref.bib index 318a181..4dd67d6 100644 --- a/ref.bib +++ b/ref.bib @@ -2309,7 +2309,7 @@ SIGNIFICANCE: Bromide is most effective and is a well-tolerated drug among DS pa number = {21}, pages = {2935--2941}, volume = {26}, - abstract = {Many species of cold-blooded animals experience substantial and rapid fluctuations in body temperature. Because biological processes are differentially temperature dependent, it is difficult to understand how physiological processes in such animals can be temperature robust [1, 2, 3, 4, 5, 6, 7, 8]. Experiments have shown that core neural circuits, such as the pyloric circuit of the crab stomatogastric ganglion (STG), exhibit robust neural activity in spite of large (20°C) temperature fluctuations [3, 5, 7, 8]. This robustness is surprising because (1) each neuron has many different kinds of ion channels with different temperature dependencies (Q10s) that interact in a highly nonlinear way to produce firing patterns and (2) across animals there is substantial variability in conductance densities that nonetheless produce almost identical firing properties. The high variability in conductance densities in these neurons [9, 10] appears to contradict the possibility that robustness is achieved through precise tuning of key temperature-dependent processes. In this paper, we develop a theoretical explanation for how temperature robustness can emerge from a simple regulatory control mechanism that is compatible with highly variable conductance densities [11, 12, 13]. The resulting model suggests a general mechanism for how nervous systems and excitable tissues can exploit degenerate relationships among temperature-sensitive processes to achieve robust function.}, + abstract = {Many species of cold-blooded animals experience substantial and rapid fluctuations in body temperature. Because biological processes are differentially temperature dependent, it is difficult to understand how physiological processes in such animals can be temperature robust [1, 2, 3, 4, 5, 6, 7, 8]. Experiments have shown that core neural circuits, such as the pyloric circuit of the crab stomatogastric ganglion (STG), exhibit robust neural activity in spite of large (20°C) temperature fluctuations [3, 5, 7, 8]. This robustness is surprising because (1) each neuron has many different kinds of ion channels with different temperature dependencies (Q10s) that interact in a highly nonlinear way to produce firing patterns and (2) across animals there is substantial variability in conductance densities that nonetheless produce almost identical firing properties. The high variability in conductance densities in these neurons [9, 10] appears to contradict the possibility that robustness is achieved through precise tuning of key temperature-dependent processes. In this paper, we develop a theoretical explanation for how temperature robustness can emerge from a simple regulatory control mechanism that is compatible with highly variable conductance densities [11, 12, 13]. The resulting model suggests a general mechanism for how nervous systems and excitable tissues can exploit degenerate relationships among temperature-sensitive processes to achieve robust function.}, doi = {10.1016/j.cub.2016.08.061}, file = {:O’Leary2016 - Temperature Robust Neural Function from Activity Dependent Ion Channel Regulation.html:URL}, keywords = {ion channels, homeostatic plasticity, temperature compensation, computational model, mathematical model, neuronal excitability, stomatogastric ganglion, crustacean, central pattern generator},