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

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 KV1.1 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.