Activation of extrasynaptic GABA_A receptors inhibits cyclothiazideinduced epileptiform activity in hippocampal CA1 neurons  

作　　者：Li Wan Xu Liu Zheng Wu Wanting Ren Shuzhen Kong Raya Abou Dargham Longzhen Cheng Yun Wang 

机构地区：[1]Institutes of Brain Science and State Key Laboratory of Medical Neurobiology [2]Neurology Department,Zhongshan Hospital,Fudan University

出　　处：《Neuroscience Bulletin》2014年第5期866-876,共11页神经科学通报（英文版）

基　　金：supported by grants from the National Natural Science Foundation of China(31129003,81100815,81171224, 81401082,and 81301108);the Science and Technology Commission of Shanghai Municipality,China(13DJ1400302, 13ZR1406500,and 11ZR1401700)

摘　　要：Extrasynaptic GABAA receptors （GABAARs）-mediated tonic inhibition is reported to involve in the patho- genesis of epilepsy. In this study, we used cyclo- thiazide （CTZ）-induced in vitro brain slice seizure model to explore the effect of selective activation of extrasynaptic GABAARS by 4,5,6,7-tetra- hydroisoxazolo[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 6-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.Extrasynaptic GABAA receptors （GABAARs）-mediated tonic inhibition is reported to involve in the patho- genesis of epilepsy. In this study, we used cyclo- thiazide （CTZ）-induced in vitro brain slice seizure model to explore the effect of selective activation of extrasynaptic GABAARS by 4,5,6,7-tetra- hydroisoxazolo[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 6-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.

关 键 词：GABAARS tonic inhibition EPILEPSY population spike CYCLOTHIAZIDE hippocampal CA1 neurons 

分 类 号：R742.1[医药卫生—神经病学与精神病学]