From 110e313f56e1522c50eac9ec03af0f30b1612d3f Mon Sep 17 00:00:00 2001 From: Jan Benda Date: Tue, 25 Apr 2023 00:34:15 +0200 Subject: [PATCH] improved rebuttal --- .../For_Submission/Koch_frontiers_revised.tex | 2 +- .../For_Submission/Koch_reviewer_comments.pdf | Bin 96019 -> 90132 bytes .../For_Submission/Koch_reviewer_comments.tex | 51 ++++-------------- 3 files changed, 11 insertions(+), 42 deletions(-) diff --git a/Frontiers_manuscript/For_Submission/Koch_frontiers_revised.tex b/Frontiers_manuscript/For_Submission/Koch_frontiers_revised.tex index 46705cd..b9ac04f 100644 --- a/Frontiers_manuscript/For_Submission/Koch_frontiers_revised.tex +++ b/Frontiers_manuscript/For_Submission/Koch_frontiers_revised.tex @@ -188,7 +188,7 @@ The effects of changes in channel properties depend in part on the neuronal mode Therefore, the transfer of LOF or GOF from the current to the firing level should be used with caution; the neuron type in which the mutant ion channel is expressed may provide valuable insight into the functional consequences of an ion channel mutation. Experimental assessment of the effects of a patient's specific ion channel mutation \textit{in vivo} is not generally feasible at a large scale. Therefore, modelling approaches investigating the effects of patient specific channelopathies provide a viable method bridging between characterization of changes in biophysical properties of ionic currents and the firing consequences of these effects. In both experimental and modelling studies on the effects of ion channel mutations on neuronal firing the specific dependency on neuron type should be considered. -Our simulations demonstrate that the effects of altered ion channel properties on firing is generally influenced by the other ionic currents present in the neuron as illustrated in Figure \ref{fig:summary}. In channelopathies the effect of a given ion channel mutation on neuronal firing therefore depends on the neuron type in which those changes occur \citep{Hedrich14874, makinson_scn1a_2016, Waxman2007, Rush2006}. Although certain complexities of neurons such as differences in neuron-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 neuron-type dependent effects on neuronal firing. The complexity and nuances of the nervous system, including neuron-type dependent firing effects of channelopathies explored here, likely underlie shortcomings in treatment approaches in patients with channelopathies. Accounting for neuron-type dependent firing effects provides an opportunity to improve the efficacy and precision in personalized medicine approaches. Although this is not experimentally feasible, improved modelling and simulations methods to predict neuron-type dependent effects may provide an opportunity to inform therapeutic strategies that are more specific and thus have greater efficacy. +Our simulations demonstrate that the effects of altered ion channel properties on firing is generally influenced by the other ionic currents present in the neuron as illustrated in Figure \ref{fig:summary}. In channelopathies the effect of a given ion channel mutation on neuronal firing therefore depends on the neuron type in which those changes occur \citep{Hedrich14874, makinson_scn1a_2016, Waxman2007, Rush2006}. Although certain complexities of neurons such as differences in neuron-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 neuron-type dependent effects on neuronal firing. The complexity and nuances of the nervous system, including neuron-type dependent firing effects of channelopathies explored here, likely underlie shortcomings in treatment approaches in patients with channelopathies. Accounting for neuron-type dependent firing effects provides an opportunity to improve the efficacy and precision in personalized medicine approaches. Although this is not experimentally feasible, improved modelling and simulation methods to predict neuron-type dependent effects may provide an opportunity to inform therapeutic strategies that are more specific and thus have greater efficacy. With this study we suggest that neuron-type specific effects are vital to a full understanding of the effects of channelopathies at the level of neuronal firing. 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