VIP interneuron impairment promotes in vivo circuit dysfunction and autism-related behaviors in Dravet syndrome

Cell Rep. 2023 Jun 27;42(6):112628. doi: 10.1016/j.celrep.2023.112628. Epub 2023 Jun 12.

Abstract

Dravet syndrome (DS) is a severe neurodevelopmental disorder caused by loss-of-function variants in SCN1A, which encodes the voltage-gated sodium channel subunit Nav1.1. We recently showed that neocortical vasoactive intestinal peptide interneurons (VIP-INs) express Nav1.1 and are hypoexcitable in DS (Scn1a+/-) mice. Here, we investigate VIP-IN function at the circuit and behavioral level by performing in vivo 2-photon calcium imaging in awake wild-type (WT) and Scn1a+/- mice. VIP-IN and pyramidal neuron activation during behavioral transition from quiet wakefulness to active running is diminished in Scn1a+/- mice, and optogenetic activation of VIP-INs restores pyramidal neuron activity to WT levels during locomotion. VIP-IN selective Scn1a deletion reproduces core autism-spectrum-disorder-related behaviors in addition to cellular- and circuit-level deficits in VIP-IN function, but without epilepsy, sudden death, or avoidance behaviors seen in the global model. Hence, VIP-INs are impaired in vivo, which may underlie non-seizure cognitive and behavioral comorbidities in DS.

Keywords: CP: Neuroscience; Dravet syndrome; Nav1.1; SCN1A; VIP interneurons; autism spectrum disorder.

Publication types

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

MeSH terms

  • Animals
  • Autistic Disorder* / genetics
  • Disease Models, Animal
  • Epilepsies, Myoclonic* / genetics
  • Interneurons / physiology
  • Mice
  • Mice, Transgenic
  • NAV1.1 Voltage-Gated Sodium Channel / genetics
  • Vasoactive Intestinal Peptide

Substances

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