Electrophysiological characterization of schizophrenia-associated variants in NaV1.2 sodium channel
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...
Main Authors: | , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Cambridge University Press
2022-06-01
|
Series: | European Psychiatry |
Subjects: | |
Online Access: | https://www.cambridge.org/core/product/identifier/S0924933822019678/type/journal_article |
_version_ | 1797617428987904000 |
---|---|
author | M. Suslova P. Hautvast A. Gaebler A. Lampert |
author_facet | M. Suslova P. Hautvast A. Gaebler A. Lampert |
author_sort | M. Suslova |
collection | DOAJ |
description |
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.
|
first_indexed | 2024-03-11T07:55:52Z |
format | Article |
id | doaj.art-98079fce5d77413faf1f141324fe8800 |
institution | Directory Open Access Journal |
issn | 0924-9338 1778-3585 |
language | English |
last_indexed | 2024-03-11T07:55:52Z |
publishDate | 2022-06-01 |
publisher | Cambridge University Press |
record_format | Article |
series | European Psychiatry |
spelling | doaj.art-98079fce5d77413faf1f141324fe88002023-11-17T05:05:48ZengCambridge University PressEuropean Psychiatry0924-93381778-35852022-06-0165S762S76210.1192/j.eurpsy.2022.1967Electrophysiological characterization of schizophrenia-associated variants in NaV1.2 sodium channelM. Suslova0P. Hautvast1A. Gaebler2A. Lampert3Uniklinik RWTH Aachen, Institute Of Physiology, Aachen, Germany Faculty of Medicine, RWTH Aachen, Department Of Psychiatry, Psychotherapy And Psychosomatics, Aachen, GermanyUniklinik RWTH Aachen, Institute Of Physiology, Aachen, GermanyUniklinik RWTH Aachen, Institute Of Physiology, Aachen, Germany Faculty of Medicine, RWTH Aachen, Department Of Psychiatry, Psychotherapy And Psychosomatics, Aachen, GermanyUniklinik RWTH Aachen, Institute Of Physiology, Aachen, Germany 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. https://www.cambridge.org/core/product/identifier/S0924933822019678/type/journal_articleschizophréniaElectrophysiologysite-directed mutagenesisVoltage-gated sodium channels |
spellingShingle | M. Suslova P. Hautvast A. Gaebler A. Lampert Electrophysiological characterization of schizophrenia-associated variants in NaV1.2 sodium channel European Psychiatry schizophrénia Electrophysiology site-directed mutagenesis Voltage-gated sodium channels |
title | Electrophysiological characterization of schizophrenia-associated variants in NaV1.2 sodium channel |
title_full | Electrophysiological characterization of schizophrenia-associated variants in NaV1.2 sodium channel |
title_fullStr | Electrophysiological characterization of schizophrenia-associated variants in NaV1.2 sodium channel |
title_full_unstemmed | Electrophysiological characterization of schizophrenia-associated variants in NaV1.2 sodium channel |
title_short | Electrophysiological characterization of schizophrenia-associated variants in NaV1.2 sodium channel |
title_sort | electrophysiological characterization of schizophrenia associated variants in nav1 2 sodium channel |
topic | schizophrénia Electrophysiology site-directed mutagenesis Voltage-gated sodium channels |
url | https://www.cambridge.org/core/product/identifier/S0924933822019678/type/journal_article |
work_keys_str_mv | AT msuslova electrophysiologicalcharacterizationofschizophreniaassociatedvariantsinnav12sodiumchannel AT phautvast electrophysiologicalcharacterizationofschizophreniaassociatedvariantsinnav12sodiumchannel AT agaebler electrophysiologicalcharacterizationofschizophreniaassociatedvariantsinnav12sodiumchannel AT alampert electrophysiologicalcharacterizationofschizophreniaassociatedvariantsinnav12sodiumchannel |