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@ -355,6 +355,8 @@ To compare the effects ion channel mutations on neuronal firing of different neu
\subsection*{Firing Frequency Analysis}
Although, firing differences can be characterized by an area under the curve of the fI curve for fixed current steps this approach characterizes firing as a mixture of key features: rheobase and the initial slope of the fI curve. By probing rheobase directly and using an AUC relative to rheobase, we disambiguate these features and enable insights into the effects on rheobase and initial fI curve steepness. This increases the specificity of our understanding of how ion channel mutations alter firing across cells types and enable classification as described in \Cref{fig:firing_characterization}. Importanty, in cases when ion channel mutations alter rheobase and initial fI curve sleepness in ways that opposing effects on firing (upper left and bottom right quadrants of \Cref{fig:firing_characterization}B) this disamgibuation is important for understanding the outcome of the mutation. In these cases, the regime the neuron is operating in is vital in determining the cells firing outcome. If it is in its excitable regime and only occasionally generates an action potential, then the effect on the rheobase is more important. If it is firing periodically with high rates, then the change in AUC might be more relevant.
\subsection*{Modelling Limitations}
The models used here are simple and while they all capture key aspects of the firing dynamics for their respective cell, they fall short of capturing the complex physiology and biophysics of real cells. However, for the purpose of understanding how different cell-types, or current environments, contribute to diversity in firing outcomes of ion channel mutations, the fidelity of the models to the physiological cells they represent is of a minor concern and the variety in currents and dynamics across models is of utmost importance. With this context, models are labelled as models A-L here to highlight that the physiological cells they represent is not of chief concern, but rather that the collection of models with different attributes results in heterogenous firing responses to the same perturbation. Additionally, the development of more realistic models is a high priority and will enable cell-type specific predictions that may aid in precision medicine approaches. Thus, weight should not be put on any single predicted firing outcome here in a specific model, but rather on the differences in outcomes that occur across the cell-type spectrum the models used here represent.
\subsection*{Neuronal Diversity}
The nervous system consists of a vastly diverse and heterogenous collection of neurons with variable properties and characteristics including diverse combinations and expression levels of ion channels which are vital for neuronal firing dynamics.
@ -381,14 +383,14 @@ Changes in delayed rectifier potassium currents, analogous to those seen in LOF
In our simulations, different current properties alter the impact of \textit{KCNA1} mutations on firing as evident in the differences seen in the impact of \(\textrm{I}_\textrm{A}\) and \IKv in the Cb stellate and STN model families on \textit{KCNA1} mutation firing. This highlights that not only knowledge of the biophysical properties of a channel but also its neuronal expression and other neuronal channels present is vital for the holistic understanding of the effects of a given ion channel mutation both at the single cell and network level.
\subsection*{Loss or Gain of Function Characterizations Do Not Fully Capture Ion Channel Mutation Effects on Firing}
The effects of changes in channel properties depend in part on the neuronal model in which they occur and can be seen in the variance of correlations (especially in AUC of the fI-curve) across models for a given current property change. Therefore, relative conductances and gating properties of currents in the ionic current environment in which an alteration in current properties occurs plays an important role in determining the outcome on firing. The use of loss of function (LOF) and gain of function (GOF) is useful at the level of ion channels to indicate whether a mutation results in more or less ionic current. However, the extension of this thinking onto whether mutations induce LOF or GOF at the level of neuronal firing based on the ionic current LOF/GOF is problematic due to the dependency of neuronal firing changes on the ionic channel environment. Thus, the direct leap from current level LOF/GOF characterizations to effects on firing without experimental or modelling-based evidence, although tempting, should be refrained from and viewed with caution when reported. This is especially relevant in the recent development of personalized medicine for channelopathies, where a patients specific channelopathy is identified and used to tailor treatments \citep{Weber2017, Ackerman2013, Helbig2020, Gnecchi2021, Musto2020, Brunklaus2022, Hedrich2021}. However, the effects of specific ion channel mutations are often characterized based on ionic currents in expression systems and classified as LOF or GOF to aid in treatment decisions \citep{johannesen_genotype-phenotype_2021, Brunklaus2022, Musto2020}. Although positive treatment outcomes occur with sodium channel blockers in patients with GOF \(\textrm{Na}_{\textrm{V}}\textrm{1.6}\) mutations, patients with both LOF and GOF \(\textrm{Na}_{\textrm{V}}\textrm{1.6}\) mutations can benefit from treatment with sodium channel blockers \citep{johannesen_genotype-phenotype_2021}, suggesting that the relationship between effects at the level of ion channels and effects at the level of firing and therapeutics is not linear or evident without further contextual information.
The effects of changes in channel properties depend in part on the neuronal model in which they occur and can be seen in the variance of correlations (especially in AUC of the fI-curve) across models for a given current property change. Therefore, relative conductances and gating properties of currents in the ionic current environment in which an alteration in current properties occurs plays an important role in determining the outcome on firing. The use of loss of function (LOF) and gain of function (GOF) is useful at the level of ion channels to indicate whether a mutation results in more or less ionic current. However, the extension of this thinking onto whether mutations induce LOF or GOF at the level of neuronal firing based on the ionic current LOF/GOF is problematic due to the dependency of neuronal firing changes on the ionic channel environment. Thus, the direct leap from current level LOF/GOF characterizations to effects on firing without experimental or modelling-based evidence, although tempting, should be refrained from and viewed with caution when reported. This is especially relevant in the recent development of personalized medicine for channelopathies, where a patient's specific channelopathy is identified and used to tailor treatments \citep{Weber2017, Ackerman2013, Helbig2020, Gnecchi2021, Musto2020, Brunklaus2022, Hedrich2021}. However, in these cases the effects of specific ion channel mutations are often characterized based on ionic currents in expression systems and classified as LOF or GOF to aid in treatment decisions \citep{johannesen_genotype-phenotype_2021, Brunklaus2022, Musto2020}. Although positive treatment outcomes occur with sodium channel blockers in patients with GOF \(\textrm{Na}_{\textrm{V}}\textrm{1.6}\) mutations, patients with both LOF and GOF \(\textrm{Na}_{\textrm{V}}\textrm{1.6}\) mutations can benefit from treatment with sodium channel blockers \citep{johannesen_genotype-phenotype_2021}, suggesting that the relationship between effects at the level of ion channels and effects at the level of firing and therapeutics is not linear or evident without further contextual information.
Therefore, this approach should be used with caution and the cell type which expresses the mutant ion channel may provide valuable insight into the functional consequences of an ion channel mutation. Where experimental assessment of the effects of a patient's specific ion channel mutation \textit{in vivo} is not feasible at a large scale, modelling approaches investigating the effects of patient specific channelopathies provides an alternative bridge between characterization of changes in biophysical properties of ionic currents and the firing consequences of these effects. In both experimental and modelling investigation into the effects of ion channel mutations on neuronal firing the specific cell-type dependency should be considered.
The effects of altered ion channel properties on firing is generally influenced by the other ionic currents present in the cell. In channelopathies the effect of a given ion channel mutation on neuronal firing therefore depends on the cell type in which those changes occur \citep{Hedrich14874, makinson_scn1a_2016, Waxman2007, Rush2006}. Although certain complexities of neurons such as differences in cell-type sensitivities to current property changes, interactions between ionic currents, cell morphology and subcellular ion channel distribution are neglected here, it is likely that this increased complexity \textit{in vivo} would contribute to the cell-type dependent effects on neuronal firing. Cell-type dependent firing effects of channelopathies may underlie shortcomings in treatment approaches in patients with channelopathies and accounting for cell-type dependent firing effects may provide an opportunity to further the efficacy and precision in personalized medicine approaches.
\subsection*{Limitations}
The models used here are simple and while they all capture key aspects of the firing dynamics for their respective cell, they fall short of capturing the complex physiology and biophysics of real cells. However, for the purpose of understanding how different cell-types, or current environments, contribute to diversity in firing outcomes of ion channel mutations, the fidelity of the models to the physiological cells they represent is of a minor concern and the variety in currents and dynamics across models is of utmost importance. With this context, models are labelled as models A-L here to highlight that the physiological cells they represent is not of chief concern, but rather that the collection of models with different attributes results in heterogenous firing responses to the same perturbation. Additionally, the development of more realistic models is a high priority and will enable cell-type specific predictions that may aid in precision medicine approaches. Thus, weight should not be put on any single predicted firing outcome here in a specific model, but rather on the differences in outcomes that occur across the cell-type spectrum the models used here represent.
The effects of altered ion channel properties on firing is generally influenced by the other ionic currents present in the cell. In channelopathies the effect of a given ion channel mutation on neuronal firing therefore depends on the cell type in which those changes occur \citep{Hedrich14874, makinson_scn1a_2016, Waxman2007, Rush2006}. Although certain complexities of neurons such as differences in cell-type sensitivities to current property changes, interactions between ionic currents, cell morphology and subcellular ion channel distribution are neglected here, it is likely that this increased complexity \textit{in vivo} would contribute to the cell-type dependent effects on neuronal firing. The complexity and nuances of the nervous system, including cell-type dependent firing effects of channelopathies explored here, likely underlie shortcomings in treatment approaches in patients with channelopathies and accounting for cell-type dependent firing effects provide an opportunity to further the efficacy and precision in personalized medicine approaches.
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