Vasoactive intestinal peptide-expressing interneurons are impaired in a mouse model of Dravet syndrome.

Kevin M Goff,Ethan M Goldberg

doi:10.7554/elife.46846

Abstract

Dravet Syndrome (DS) is a severe neurodevelopmental disorder caused by pathogenic loss of function variants in the gene SCN1A which encodes the voltage gated sodium (Na+) channel subunit Nav1.1. GABAergic interneurons expressing parvalbumin (PV-INs) and somatostatin (SST-INs) exhibit impaired excitability in DS (Scn1a+/-) mice. However, the function of a third major class of interneurons in DS - those expressing vasoactive intestinal peptide (VIP-IN) -is unknown. We recorded VIP-INs in brain slices from Scn1a+/-mice and wild-type littermate controls and found prominent impairment of irregular spiking (IS), but not continuous adapting (CA) VIP-INs, in Scn1a+/- mice. Application of the Nav1.1-specific toxin Hm1a rescued the observed deficits. The IS vs. CA firing pattern is determined by expression of KCNQ channels; IS VIP-INs switched to tonic firing with both pharmacologic blockade of M-current and muscarinic acetylcholine receptor activation. These results show that VIP-INs express Nav1.1 and are dysfunctional in DS, which may contribute to DS pathogenesis.

Highlights

Dravet syndrome (DS) is a severe neurodevelopmental disorder characterized by temperature-sensitive and spontaneous seizures in the first year of life followed by progression to intractable epilepsy, intellectual disability with autistic features, and a markedly increased rate of sudden unexpected death (SUDEP) (Genton et al, 2011; Kalume et al, 2013; Oakley et al, 2009; Scheffer, 2012)
In the course of these initial experiments, we observed a subset (~50%) of VIP-INs in Scn1a+/- mice that only fired a brief train of action potential (AP) before complete cessation of firing (Figure 1A), which was atypical for VIP-INs from WT mice
We identified a diversity of VIP-IN firing patterns in response to step depolarizations consistent with previously described continuous adapting (CA), irregular spiking (IS), and bursting cells

Summary

Introduction

Dravet syndrome (DS) is a severe neurodevelopmental disorder characterized by temperature-sensitive and spontaneous seizures in the first year of life followed by progression to intractable epilepsy, intellectual disability with autistic features, and a markedly increased rate of sudden unexpected death (SUDEP) (Genton et al, 2011; Kalume et al, 2013; Oakley et al, 2009; Scheffer, 2012). We recently showed that PV-IN hypoexcitability in Scn1a+/- mice is restricted to an early and transient developmental window (P11-21), with subsequent normalization of high-frequency action potential discharge by P35 (Favero et al, 2018) This finding encourages a reconsideration of the cellular basis of circuit pathology that underlies chronic epilepsy and epilepsy-associated cognitive abnormalities in DS. Muscarinic, but not nicotinic cholinergic receptor activation reversibly converted IS VIP-INs to a continuous firing mode Overall, these results identify a novel cellular locus of dysfunction in DS that may relate to the profound and durable cognitive impairments observed in human patients (Genton et al, 2011; Scheffer, 2012; Villas et al, 2017) and refines our understanding of the diversity of VIP-INs and the molecular determinants of VIP-IN function

Results

Discussion

Materials and methods

P imaging and morphological reconstruction

Funding Funder