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Electrophysiological characterization of schizophrenia-associated variants in NaV1.2 sodium channel

Published online by Cambridge University Press:  01 September 2022

M. Suslova*
Affiliation:
Uniklinik RWTH Aachen, Institute Of Physiology, Aachen, Germany Faculty of Medicine, RWTH Aachen, Department Of Psychiatry, Psychotherapy And Psychosomatics, Aachen, Germany
P. Hautvast
Affiliation:
Uniklinik RWTH Aachen, Institute Of Physiology, Aachen, Germany
A. Gaebler
Affiliation:
Uniklinik RWTH Aachen, Institute Of Physiology, Aachen, Germany Faculty of Medicine, RWTH Aachen, Department Of Psychiatry, Psychotherapy And Psychosomatics, Aachen, Germany
A. Lampert
Affiliation:
Uniklinik RWTH Aachen, Institute Of Physiology, Aachen, Germany
*
*Corresponding author.

Abstract

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Introduction

A major pathophysiological hypothesis of schizophrenia states an increased activity of glutamatergic neurons leading to an imbalance of neural excitation and inhibition (E/I-imbalance). One potential molecular mechanism of E/I-imbalance is a dysfunction of voltage-gated sodium channels, which are crucial for the generation of action potentials, the fundamental event of neuronal excitation. Indeed, patients with schizophrenia exhibit an increased burden of rare exonic variants of sodium channel genes, but the literature describing their electrophysiological effect is scarce.

Objectives

The aim of this project is to assess the functional impact of three mutations of the Sodium Voltage-Gated Channel Alpha Subunit 2 (SCN2A) gene / NaV1.2 channel which were identified in four patients with schizophrenia, using a heterologous expression system.

Methods

Three variants of the human SCN2A gene (R850P, V1282F and S1656P) were created using site-directed mutagenesis. HEK293T cells transfected with either the mutant or wild type constructs are being investigated by voltage-clamp technique, applying activation, steady-state fast inactivation, use dependency and ramp protocols.

Results

All three mutated constructs were successfully created. Preliminary recordings from the V1282F mutant indicate a shift of both the activation and steady-state fast inactivation to the hyperpolarized direction.

Conclusions

In a subgroup of patients, E/I imbalance may be a consequence of Nav1.2 mutations leading to increased excitability of glutamatergic neurons. By integrating insights from different mutations we aim to identify traits of a potentially shared disease pathway which may provide a basis for the development of novel therapeutics.

Disclosure

No significant relationships.

Type
Abstract
Creative Commons
Creative Common License - CCCreative Common License - BY
This is an Open Access article, distributed under the terms of the Creative Commons Attribution licence (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted re-use, distribution, and reproduction in any medium, provided the original work is properly cited.
Copyright
© The Author(s), 2022. Published by Cambridge University Press on behalf of the European Psychiatric Association
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