Activation of extrasynaptic GABAA receptors inhibits cyclothiazide-induced epileptiform activity in hippocampal CA1 neurons
Activation of extrasynaptic GABAA receptors inhibits cyclothiazide-induced epileptiform activity in hippocampal CA1 neurons
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DOI：
10.1007/s12264-014-1466-8
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发表时间：
2014-09
影响因子：
5.6
通讯作者：
Li Wan;Xu Liu;Zheng Wu;Wanting Ren;Shuzhen Kong;Raya Abou Dargham;Longzhen Cheng;Yun Wang
中科院分区：
文献类型：
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作者：
Li Wan;Xu Liu;Zheng Wu;Wanting Ren;Shuzhen Kong;Raya Abou Dargham;Longzhen Cheng;Yun Wang
突触外GABA受体(GABAARs)介导的紧张性抑制被报道参与癫痫的发病机制。在本研究中，我们在体外脑片惊厥模型上观察了4，5，6，7-四氢异恶唑[5，4-c]吡啶-3-醇(THIP)选择性激活突触外GABA受体对CTZ诱导的海马神经元癫痫样活动的影响。CTZ灌流可剂量依赖性地诱导CA1区锥体神经元诱发群峰电位的多个癫痫样峰，而THIP(5μ/L)可显著减少刺激CTZ所致的多个PS峰。Western印迹结果显示，CTZ作用2 h后，突触外特异的GABAAR亚基δ亚基在细胞膜上的表达也显著下调。我们的结果提示，突触外GABAARs的激活抑制了CTZ诱导的CA1区神经元的癫痫样活动，进一步支持了突触外GABAARs介导的紧张性抑制在癫痫发生中起重要作用的假说。
Extrasynaptic GABAAreceptors (GABAARs)-mediated tonic inhibition is reported to involve in the pathogenesis of epilepsy. In this study, we used cyclothiazide (CTZ)-inducedin vitrobrain slice seizure model to explore the effect of selective activation of extrasynaptic GABAARs by 4,5,6,7-tetrahydroisoxazolo[5,4-c] pyridine-3-ol (THIP) on the CTZ-induced epileptiform activity in hippocampal neurons. Perfusion with CTZ dose-dependently induced multiple epileptiform peaks of evoked population spikes (PSs) in CA1 pyramidal neurons, and treatment with THIP (5 μmol/L) significantly reduced the multiple PS peaks induced by CTZ stimulation. Western blot showed that the δ-subunit of the GABAAR, an extrasynaptic specific GABAAR subunit, was also significantly down-regulated in the cell membrane 2 h after CTZ treatment. Our results suggest that the CTZ-induced epileptiform activity in hippocampal CA1 neurons is suppressed by the activation of extrasynaptic GABAARs, and further support the hypothesis that tonic inhibition mediated by extrasynaptic GABAARs plays a prominent role in seizure generation.