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

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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.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Figure 3, Table 1 and Figure 8.

The following previously published data sets were used

1. Allen Institute for Brain Science
(2015) Allen Cell Types Database
Allen Brain Institute: celltypes.brain-map.org/rnaseq.

https://cdn.elifesciences.org/articles/46846/celltypes.brain-map.org/rnaseq

Article and author information

Author details

Kevin Mitchell Goff

Department of Neuroscience, The University of Pennsylvania, Philadelphia, United States

Competing interests
The authors declare that no competing interests exist.
Ethan Michael Goldberg

Department of Neuroscience, The University of Pennsylvania, Philadelphia, United States

For correspondence
goldberge@email.chop.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-7404-735X

Funding

National Institute of Neurological Disorders and Stroke (K08 NS097633)

Ethan Michael Goldberg

Burroughs Wellcome Fund (Career Award for Medical Scientists)

Ethan Michael Goldberg

National Institute of Neurological Disorders and Stroke (R01 NS110869)

Ethan Michael Goldberg

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocol (#1152) of The Children's Hospital of Philadelphia. The protocol was approved by the IACUC Committee of The Children's Hospital of Philadelphia. All surgery was performed under isoflurane anesthesia, and every effort was made to minimize suffering.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.