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

Elife. 2019 Jul 8;8:e46846. 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.

Keywords: Nav1.1; SCN1A; electrophysiology; epilepsy; ion channels; mouse; neuroscience.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / genetics
  • Action Potentials / physiology
  • Animals
  • Brain / metabolism*
  • Brain / physiopathology
  • Epilepsies, Myoclonic / genetics
  • Epilepsies, Myoclonic / metabolism*
  • Epilepsies, Myoclonic / physiopathology
  • Interneurons / metabolism*
  • Interneurons / physiology
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • NAV1.1 Voltage-Gated Sodium Channel / genetics
  • NAV1.1 Voltage-Gated Sodium Channel / metabolism
  • Vasoactive Intestinal Peptide / genetics
  • Vasoactive Intestinal Peptide / metabolism*

Substances

  • NAV1.1 Voltage-Gated Sodium Channel
  • Scn1a protein, mouse
  • Vasoactive Intestinal Peptide