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

• Main Authors: 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
• Format: Article
• Language: English
• Published: Elsevier 2009-03-01
• Series: Neurobiology of Disease
• Subjects: Hyperpolarization-activated cyclic nucleotide-gated channels; Seizure; Ethosuximide; Ataxia; HCN2; HCN1
• Online Access: http://www.sciencedirect.com/science/article/pii/S0969996108003082

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.