Absence epilepsy in apathetic, a spontaneous mutant mouse lacking the h channel subunit, HCN2

Wendy K. Chung, Minyoung Shin, Thomas C. Jaramillo, Rudolph L. Leibel, Charles A. LeDuc, Stuart G. Fischer, Efthia Tzilianos, Ayman A. Gheith, Alan S. Lewis, Dane M. Chetkovich*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

58 Scopus citations

Abstract

Analysis of naturally occurring mutations that cause seizures in rodents has advanced understanding of the molecular mechanisms underlying epilepsy. Abnormalities of Ih and h channel expression have been found in many animal models of absence epilepsy. We characterized a novel spontaneous mutant mouse, apathetic (ap/ap), and identified the ap mutation as a 4 base pair insertion within the coding region of Hcn2, the gene encoding the h channel subunit 2 (HCN2). We demonstrated that Hcn2ap mRNA is reduced by 90% compared to wild type, and the predicted truncated HCN2ap protein is absent from the brain tissue of mice carrying the ap allele. ap/ap mice exhibited ataxia, generalized spike-wave absence seizures, and rare generalized tonic-clonic seizures. ap/+ mice had a normal gait, occasional absence seizures and an increased severity of chemoconvulsant-induced seizures. These findings help elucidate basic mechanisms of absence epilepsy and suggest HCN2 may be a target for therapeutic intervention.

Original languageEnglish (US)
Pages (from-to)499-508
Number of pages10
JournalNeurobiology of Disease
Volume33
Issue number3
DOIs
StatePublished - Mar 2009

Keywords

  • Ataxia
  • Ethosuximide
  • HCN1
  • HCN2
  • HCN4
  • Human chromosome 19p13.3
  • Hyperpolarization-activated cyclic nucleotide-gated channels
  • Mouse chromosome 10
  • Seizure

ASJC Scopus subject areas

  • Neurology

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