Cope David W, Di Giovanni Giuseppe, Fyson Sarah J, Orbán Gergely, Errington Adam C, Lorincz Magor L, Gould Timothy M, Carter David A, Crunelli Vincenzo
School of Biosciences, Cardiff University, Cardiff, UK.
Nat Med. 2009 Dec;15(12):1392-8. doi: 10.1038/nm.2058. Epub 2009 Nov 22.
The cellular mechanisms underlying typical absence seizures, which characterize various idiopathic generalized epilepsies, are not fully understood, but impaired gamma-aminobutyric acid (GABA)-ergic inhibition remains an attractive hypothesis. In contrast, we show here that extrasynaptic GABA(A) 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 crucial in governing seizure genesis. Extrasynaptic GABA(A) receptors are a requirement for seizures in two of the best characterized models of absence epilepsy, and the selective activation of thalamic extrasynaptic GABA(A) receptors is sufficient to elicit both electrographic and behavioral correlates of seizures in normal rats. These results identify an apparently common cellular pathology in typical absence seizures that may have epileptogenic importance and highlight potential therapeutic targets for the treatment of absence epilepsy.
典型失神发作是各种特发性全身性癫痫的特征，其潜在的细胞机制尚未完全明确，但γ-氨基丁酸（GABA）能抑制受损仍是一个有吸引力的假说。相比之下，我们在此表明，在来自多种失神发作的遗传和药理学模型的丘脑皮质神经元中，突触外GABA(A)受体依赖性“强直”抑制增强。强直抑制增强是由于在测试的遗传模型中，GABA转运体GAT-1对GABA的摄取受损，并且GAT-1在控制癫痫发作的发生中起关键作用。在两个特征最明确的失神癫痫模型中，突触外GABA(A)受体是癫痫发作的必要条件，并且选择性激活丘脑突触外GABA(A)受体足以在正常大鼠中引发癫痫发作的脑电图和行为相关表现。这些结果确定了典型失神发作中一种明显常见的细胞病理学，其可能具有致痫重要性，并突出了失神癫痫治疗的潜在靶点。
