Enhanced tonic GABAA inhibition in typical absence epilepsy.
Enhanced tonic GABAA inhibition in typical absence epilepsy.
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DOI：
10.1038/nm.2058
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发表时间：
2009-12
期刊：
影响因子：
82.9
通讯作者：
Crunelli, Vincenzo
中科院分区：
文献类型：
--
作者：
Cope, David W.;Di Giovanni, Giuseppe;Fyson, Sarah J.;Orban, Gergely;Errington, Adam C.;Lorincz, Magor L.;Gould, Timothy M.;Carter, David A.;Crunelli, Vincenzo
各种特发性全身性癫痫的典型失神发作背后的细胞机制尚不完全清楚，但GABA能抑制受损仍是一个有吸引力的假说。相反，我们在这里展示了突触外依赖GABAA受体的‘紧张性’抑制在丘脑皮质神经元中增加，来自不同的失神发作的遗传和药理学模型。在所测试的遗传模型中，紧张性抑制的增加是由于GABA转运体GAT-1对GABA的摄取受损，而GAT-1在控制癫痫的发生中起关键作用。在两种特征最佳的失神癫痫模型中，突触外GABAA受体是癫痫发作所必需的，选择性激活丘脑突触外GABAA受体足以引起正常动物癫痫发作的电信号和行为相关。这些结果确定了典型失神发作的一种明显常见的细胞病理学，可能具有致痫意义，并突出了治疗失神癫痫的新治疗靶点。
The cellular mechanisms underlying typical absence seizures, which characterize various idiopathic generalized epilepsies, are not fully understood, but impaired GABAergic inhibition remains an attractive hypothesis. In contrast, we show here that extrasynaptic GABAA receptor–dependent ‘tonic’ inhibition is increased in thalamocortical neurons from diverse genetic and pharmacological models of absence seizures. Increased tonic inhibition is due to compromised GABA uptake by the GABA transporter GAT–1 in the genetic models tested, and GAT–1 is critical in governing seizure genesis. Extrasynaptic GABAA receptors are a requirement for seizures in two of the best characterized models of absence epilepsy, and the selective activation of thalamic extrasynaptic GABAA receptors is sufficient to elicit both electrographic and behavioural correlates of seizures in normal animals. These results identify an apparently common cellular pathology in typical absence seizures that may have epileptogenic significance, and highlight novel therapeutic targets for the treatment of absence epilepsy.
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