Developmentally regulated impairment of parvalbumin interneuron synaptic transmission in an experimental model of Dravet syndrome

Keisuke Kaneko, Christopher B. Currin, Kevin M. Goff, Eric R. Wengert, Ala Somarowthu, Tim P. Vogels, Ethan M. Goldberg

Research output: Contribution to journalArticlepeer-review

15 Citations (Scopus)

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.

Original languageEnglish
Article number110580
JournalCell Reports
Volume38
Issue number13
DOIs
Publication statusPublished - 29 Mar 2022
Externally publishedYes

Keywords

  • CP: Neuroscience
  • Dravet syndrome
  • GABAergic interneurons
  • Nav1.1
  • SCN1A
  • epilepsy

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