Developmentally Regulated Impairment of Parvalbumin Interneuron Synaptic Transmission in an Experimental Model of Dravet Syndrome

Overview

Journal Cell Rep

Publisher Cell Press

Specialties Biology
Cell Biology
Molecular Biology

Date 2022 Mar 30

PMID 35354025

Authors

Keisuke Kaneko

Christopher B Currin

Kevin M Goff

Eric R Wengert

Ala Somarowthu

Tim P Vogels

Ethan M Goldberg

Affiliations

Soon will be listed here.

Abstract

Dravet syndrome is a neurodevelopmental disorder characterized by epilepsy, intellectual disability, and sudden death due to pathogenic variants in SCN1A with loss of function of the sodium channel subunit Nav1.1. Nav1.1-expressing parvalbumin GABAergic interneurons (PV-INs) from young Scn1a mice show impaired action potential generation. An approach assessing PV-IN function in the same mice at two time points shows impaired spike generation in all Scn1a mice at postnatal days (P) 16-21, whether deceased prior or surviving to P35, with normalization by P35 in surviving mice. However, PV-IN synaptic transmission is dysfunctional in young Scn1a mice that did not survive and in Scn1a mice ≥ P35. Modeling confirms that PV-IN axonal propagation is more sensitive to decreased sodium conductance than spike generation. These results demonstrate dynamic dysfunction in Dravet syndrome: combined abnormalities of PV-IN spike generation and propagation drives early disease severity, while ongoing dysfunction of synaptic transmission contributes to chronic pathology.

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