Loss or gain of function? Effects of ion channel mutations on neuronal firing depend on the neuron type

Nils A Koch; Lukas Sonnenberg; Ulrike B S Hedrich; Stephan Lauxmann; Jan Benda

doi:10.3389/fneur.2023.1194811

Loss or gain of function? Effects of ion channel mutations on neuronal firing depend on the neuron type

Front Neurol. 2023 May 24:14:1194811. doi: 10.3389/fneur.2023.1194811. eCollection 2023.

Authors

Nils A Koch^{1

2}, Lukas Sonnenberg^{1

2}, Ulrike B S Hedrich³, Stephan Lauxmann^{1

3}, Jan Benda^{1

2}

Affiliations

¹ Institute of Neurobiology, Faculty of Mathematics and Natural Sciences, University of Tübingen, Tübingen, Germany.
² Bernstein Center for Computational Neuroscience Tübingen, Tübingen, Germany.
³ Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.

Abstract

Introduction: Clinically relevant mutations to voltage-gated ion channels, called channelopathies, alter ion channel function, properties of ionic currents, and neuronal firing. The effects of ion channel mutations are routinely assessed and characterized as loss of function (LOF) or gain of function (GOF) at the level of ionic currents. However, emerging personalized medicine approaches based on LOF/GOF characterization have limited therapeutic success. Potential reasons are among others that the translation from this binary characterization to neuronal firing is currently not well-understood-especially when considering different neuronal cell types. In this study, we investigate the impact of neuronal cell type on the firing outcome of ion channel mutations.

Methods: To this end, we simulated a diverse collection of single-compartment, conductance-based neuron models that differed in their composition of ionic currents. We systematically analyzed the effects of changes in ion current properties on firing in different neuronal types. Additionally, we simulated the effects of known mutations in KCNA1 gene encoding the K_V1.1 potassium channel subtype associated with episodic ataxia type 1 (EA1).

Results: These simulations revealed that the outcome of a given change in ion channel properties on neuronal excitability depends on neuron type, i.e., the properties and expression levels of the unaffected ionic currents.

Discussion: Consequently, neuron-type specific effects are vital to a full understanding of the effects of channelopathies on neuronal excitability and are an important step toward improving the efficacy and precision of personalized medicine approaches.

Keywords: ataxia; channelopathies; conductance-based models; epilepsy; neuronal heterogeneity; neuronal simulation; potassium currents.

Grants and funding

This work was supported by the German Research Foundation in the Frame of the Research Unit FOR-2715 (DFG, Grants Le1030/15-1/2 and HE 8155/1-2) and the Network for Rare Ion Channel Disorders Treat-ION of the Federal Ministry for Education and Research (BMBF, Grants 01GM1907A and 01GM2210A). SL was supported with an Otfrid-Foerster stipend from the German Society for Epileptology (DGfE).