Genetic Enhancement of Thalamocortical Network Activity by Elevating α1G-Mediated Low-Voltage-Activated Calcium Current Induces Pure Absence Epilepsy
Genetic Enhancement of Thalamocortical Network Activity by Elevating α1G-Mediated Low-Voltage-Activated Calcium Current Induces Pure Absence Epilepsy
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DOI：
10.1523/jneurosci.2081-08.2009
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发表时间：
2009-02-11
影响因子：
5.3
通讯作者：
Noebels, Jeffrey L.
中科院分区：
文献类型：
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作者：
Ernst, Wayne L.;Zhang, Yi;Noebels, Jeffrey L.
失神发作是儿童癫痫的主要形式。人类和小鼠P/Q型钙通道基因突变引发复杂的失神癫痫和共济失调表型，并在小鼠中，继发性升高神经元低电压激活的T型钙电流。这些电流影响丘脑皮层网络活动，并有助于产生与失神发作相关的皮层棘波放电（SWD）。为了解决增强的丘脑皮层T型电流是否足以诱导癫痫表型，产生了两个BAC转基因小鼠品系，过表达α 1GT型钙通道的Cacna 1g基因，具有低和高转基因拷贝数，表现出升高的α 1G表达，并表现出增加的功能性T型电流在丘脑神经元中测量。这两条线表现出频繁的双边皮质SWD与行为逮捕，但缺乏其他明显的神经异常。这些模型提供了第一个证据表明，脑T型电流的原发性升高与纯粹的失神癫痫有因果关系，并选择性地确定Cacna 1g，三个T型钙通道基因之一，作为一个遗传复杂的致癫痫途径的关键组成部分。
Absence seizures are a leading form of childhood epilepsy. Human and mouse P/Q-type calcium channel gene mutations initiate a complex absence epilepsy and ataxia phenotype, and in mice, secondarily elevate neuronal low-voltage-activated T-type calcium currents. These currents influence thalamocortical network activity and contribute to the generation of cortical spike-wave discharges (SWDs) associated with absence seizures. To address whether enhanced thalamocortical T-type currents suffice to induce an epileptic phenotype, two BAC transgenic mouse lines overexpressing the Cacna1g gene for alpha 1GT-type calcium channels were generated with low and high transgene copy numbers that exhibit elevated alpha 1G expression and showed increased functional T-type currents measured in thalamic neurons. Both lines exhibit frequent bilateral cortical SWDs associated with behavioral arrest but lack other overt neurological abnormalities. These models provide the first evidence that primary elevation of brain T-type currents are causally related to pure absence epilepsy, and selectively identify Cacna1g, one of the three T-type calcium channel genes, as a key component of a genetically complex epileptogenic pathway.