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

Neurobiol Dis. 2009 Mar;33(3):499-508. doi: 10.1016/j.nbd.2008.12.004. Epub 2008 Dec 25.

Abstract

Analysis of naturally occurring mutations that cause seizures in rodents has advanced understanding of the molecular mechanisms underlying epilepsy. Abnormalities of I(h) 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 Hcn2(ap) mRNA is reduced by 90% compared to wild type, and the predicted truncated HCN2(ap) 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Ataxia / genetics
  • Base Sequence
  • Body Size
  • Brain / metabolism
  • Brain / physiopathology
  • COS Cells
  • Chlorocebus aethiops
  • Convulsants / administration & dosage
  • Cyclic Nucleotide-Gated Cation Channels / genetics
  • Cyclic Nucleotide-Gated Cation Channels / metabolism
  • Epilepsy, Absence / genetics*
  • Epilepsy, Absence / physiopathology
  • Female
  • Frameshift Mutation
  • Gait
  • Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
  • Ion Channels / chemistry
  • Ion Channels / genetics*
  • Male
  • Mice
  • Mice, Mutant Strains
  • Molecular Sequence Data
  • Phenotype
  • Potassium Channels / genetics
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Seizures / chemically induced
  • Seizures / genetics

Substances

  • Convulsants
  • Cyclic Nucleotide-Gated Cation Channels
  • Hcn2 protein, mouse
  • Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
  • Ion Channels
  • Potassium Channels
  • RNA, Messenger