Absence epilepsy in apathetic

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• 作者：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
• 关键词：Hyperpolarization-activated cyclic nucleotide-gated channels ; Seizure ; Ethosuximide ; Ataxia ; HCN2 ; HCN1 ; HCN4 ; Mouse chromosome 10 ; Human chromosome 19p13.3
• 刊名：Neurobiology of Disease
• 出版年：2009
• 出版时间：March 2009
• 年：2009
• 卷：33
• 期：3
• 页码：499-508
• 全文大小：1018 K

文摘

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.