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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Reduced cortical inhibition in a mouse model of familial childhood absence epilepsy
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Reduced cortical inhibition in a mouse model of familial childhood absence epilepsy

机译：在家族性儿童期失神癫痫小鼠模型中皮质抑制作用降低

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摘要

Mutations in the GABA_A receptor γ2 subunit are associated with childhood absence epilepsy and febrile seizures. To understand better the molecular basis of absence epilepsy in man, we developed a mouse model harboring a γ2 subunit point mutation (R43Q) found in a large Australian family. Mice heterozygous for the mutation demonstrated behavioral arrest associated with 6-to 7-Hz spike-and-wave discharges, which are blocked by ethosuximide, a first-line treatment for absence epilepsy in man. Seizures in the mouse showed an abrupt onset at around age 20 days corresponding to the childhood nature of this disease. Reduced cell surface expression of γ2(R43Q) was seen in heterozygous mice in the absence of any change in α1 3 subunit surface expression, ruling out a dominant-negative effect. GABA_(A~-) mediated synaptic currents recorded from cortical pyramidal neurons revealed a small but significant reduction that was not seen in the reticular or ventrobasal thalamic nuclei. We hypothesize that a subtle reduction in cortical inhibition underlies childhood absence epilepsy seen in humans harboring the R43Q mutation.
机译：GABA_A受体γ2亚基的突变与儿童失神癫痫和高热惊厥有关。为了更好地了解人类失神癫痫的分子基础，我们开发了一种小鼠模型，该模型带有一个在澳大利亚大家庭中发现的γ2亚基点突变（R43Q）。杂合子突变的小鼠表现出与6至7 Hz尖峰和波放电相关的行为停滞，而后者被ethosuximide阻断，后者是人类失神癫痫的一线治疗药物。小鼠的癫痫发作在20天左右突然发作，这与这种疾病的儿童时期有关。在杂合小鼠中，在α13亚基表面表达没有任何变化的情况下，观察到γ2（R43Q）细胞表面表达降低，排除了显性负效应。皮质锥体神经元记录的GABA_（A〜-）介导的突触电流显示出较小但明显的减少，这在网状或室基底丘脑核中未见。我们假设皮质抑制作用的轻微降低是在携带R43Q突变的人类中所见的儿童期癫痫病的基础。

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