A transient developmental window of fast-spiking interneuron dysfunction in a mouse model of dravet syndrome

Morgana Favero, Nathaniel P. Sotuyo, Emily Lopez, Jennifer A. Kearney, Ethan M. Goldberg*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

32 Scopus citations

Abstract

Dravet syndrome is a severe, childhood-onset epilepsy largely due to heterozygous loss-of-function mutation of the gene SCN1A, which encodes the type 1 neuronal voltage-gated sodium (Na + ) channel α subunit Nav1.1. Prior studies in mouse models of Dravet syndrome (Scn1a +/- mice) indicate that, in cerebral cortex, Nav1.1 is predominantly expressed in GABAergic interneurons, in particular in parvalbumin-positive fast-spiking basket cell interneurons (PVINs). This has led to a model of Dravet syndrome pathogenesis in which Nav1.1 mutation leads to preferential dysfunction of interneurons, decreased synaptic inhibition, hyperexcitability, and epilepsy. However, such studies have been implemented at early developmental time points. Here, we performed electrophysiological recordings in acute brain slices prepared from male and female Scn1a +/- mice as well as age-matched wild-type littermate controls and found that, later in development, the excitability of PVINs had normalized. Analysis of action potential waveforms indirectly suggests a reorganization of axonal Na + channels in PVINs from Scn1a +/- mice, a finding supported by immunohistochemical data showing elongation of the axon initial segment. Our results imply that transient impairment of action potential generation by PVINs may contribute to the initial appearance of epilepsy, but is not the mechanism of ongoing, chronic epilepsy in Dravet syndrome.

Original languageEnglish (US)
Pages (from-to)7912-7927
Number of pages16
JournalJournal of Neuroscience
Volume38
Issue number36
DOIs
StatePublished - Sep 5 2018

Keywords

  • Dravet syndrome
  • Epilepsy
  • Fast-spiking interneurons
  • Interneurons
  • Nav1.1
  • SCN1A

ASJC Scopus subject areas

  • Neuroscience(all)

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