Impairment of sharp-wave ripples in a murine model of dravet syndrome

Christine S. Cheah, Brian N. Lundstrom, William A. Catteral, John C. Oakley

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Dravet syndrome (DS) is a severe early-onset epilepsy associated with heterozygous loss-of-function mutations in SCN1A. Animal models of DS with global Scn1a haploinsufficiency recapitulate the DS phenotype, including seizures, premature death, and impaired spatial memory performance. Spatial memory requires hippocampal sharp-wave ripples (SPW-Rs), which consist of high-frequency field potential oscillations (ripples, 100-260 Hz) superimposed on a slower SPW. Published in vitro electrophysiologic recordings in DS mice demonstrate reduced firing of GABAergic inhibitory neurons, which are essential for the formation of SPW-R complexes. Here, in vivo electrophysiologic recordings of hippocampal local field potential in both male and female mice demonstrate that Scn1a haploinsufficiency slows intrinsic ripple frequency and reduces the rate of SPW-R occurrence. In DS mice, peak ripple-band power is shifted to lower frequencies, average intertrough intervals of individually detected ripples are slower, and the rate of SPW-R generation is reduced, while SPW amplitude remains unaffected. These alterations in SPW-R properties, in combination with published reductions in interneuron function in DS, suggest a direct link between reduced inhibitory neuron excitability and impaired SPW-R function. A simple interconnected, conductance-based in silico interneuron networkmodel was usedto determine whether reduced sodium conductanceis sufficient to slow ripple frequency, and stimulation with a modeled SPW demonstratesthat reduced sodium conductance alone is sufficientto slow oscillatory frequencies. These findings forge a potential mechanistic link between impaired SPW-R generation and Scn1amutation in DS mice, expanding the set of disorders in which SPW-R dysfunction contributes to impaired memory.

Original languageEnglish (US)
Pages (from-to)9251-9260
Number of pages10
JournalJournal of Neuroscience
Volume39
Issue number46
DOIs
StatePublished - Nov 13 2019

Keywords

  • Channelopathy
  • Dravet Syndrome
  • Epilepsy Comorbidity
  • Learning And Memory
  • Scn1A
  • Sharp-Wave Ripple

ASJC Scopus subject areas

  • Neuroscience(all)

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