Absence epilepsy in apathetic, a spontaneous mutant mouse lacking the h channel subunit, HCN2.
Absence epilepsy in apathetic, a spontaneous mutant mouse lacking the h channel subunit, HCN2.
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DOI：
10.1016/j.nbd.2008.12.004
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发表时间：
2009-03
影响因子：
6.1
通讯作者：
Chetkovich DM
中科院分区：
文献类型：
--
作者：
Chung WK;Shin M;Jaramillo TC;Leibel RL;LeDuc CA;Fischer SG;Tzilianos E;Gheith AA;Lewis AS;Chetkovich DM
对啮齿类动物中引起癫痫发作的自然发生的突变的分析促进了对癫痫潜在分子机制的理解。在许多失神癫痫动物模型中发现了Ih和h通道表达的异常。我们的特点是一种新的自发突变小鼠，冷漠（ap/ap），并确定了ap突变作为一个4碱基对插入HCN 2，编码h通道亚基2（HCN 2）的基因的编码区。我们证明了Hcn 2ap mRNA与野生型相比减少了90%，并且携带ap等位基因的小鼠的脑组织中不存在预测的截短的HCN 2ap蛋白。AP/AP小鼠表现出共济失调、全身性棘波缺失发作和罕见的全身性强直阵挛发作。AP/+小鼠具有正常步态、偶尔失神发作和化学惊厥剂诱导的发作的严重程度增加。这些发现有助于阐明失神癫痫的基本机制，并表明HCN 2可能是治疗干预的靶点。
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.
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