Reduced cortical inhibition in a mouse model of familial childhood absence epilepsy

Heneu O. Tan, Christopher A. Reid, Frank N. Single, Philip J. Davies, Cindy Chiu, Susan Murphy, Alison L. Clarke, Leanne Dibbens, Heinz Krestel, John C. Mulley, Mathew V. Jones, Peter H. Seeburg, Bert Sakmann, Samuel F. Berkovic, Rolf Sprengel, Steven Petrou

Research output: Contribution to journalArticlepeer-review

145 Citations (Scopus)

Abstract

Mutations in the GABAA receptor γ2 subunit are associated with childhood absence epilepsy and febrile seizures. To understand better the molecular basis of absence epilepsy in man, we developed a mouse model harboring a γ2 subunit point mutation (R43Q) found in a large Australian family. Mice heterozygous for the mutation demonstrated behavioral arrest associated with 6-to 7-Hz spike-and-wave discharges, which are blocked by ethosuximide, a first-line treatment for absence epilepsy in man. Seizures in the mouse showed an abrupt onset at around age 20 days corresponding to the childhood nature of this disease. Reduced cell surface expression of γ2(R43Q) was seen in heterozygous mice in the absence of any change in α1 subunit surface expression, ruling out a dominant-negative effect. GABAA-mediated synaptic currents recorded from cortical pyramidal neurons revealed a small but significant reduction that was not seen in the reticular or ventrobasal thalamic nuclei. We hypothesize that a subtle reduction in cortical inhibition underlies childhood absence epilepsy seen in humans harboring the R43Q mutation.

Original languageEnglish
Pages (from-to)17536-17541
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number44
DOIs
Publication statusPublished - 2007 Oct 30

Keywords

  • Electroencephalogram
  • GABA receptor
  • Genetics
  • Synapse
  • Trafficking

ASJC Scopus subject areas

  • General

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