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. 2014 Sep 28;30(5):866–876. doi: 10.1007/s12264-014-1466-8

Activation of extrasynaptic GABAA receptors inhibits cyclothiazide-induced epileptiform activity in hippocampal CA1 neurons

Li Wan 1, Xu Liu 2, Zheng Wu 1, Wanting Ren 1, Shuzhen Kong 1, Raya Abou Dargham 1, Longzhen Cheng 1,✉, Yun Wang 1,✉
PMCID: PMC5562591  PMID: 25260800

Abstract

Extrasynaptic GABAA receptors (GABAARs)-mediated tonic inhibition is reported to involve in the pathogenesis of epilepsy. In this study, we used cyclothiazide (CTZ)-induced in vitro brain 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.

Keywords: GABAARs, tonic inhibition, epilepsy, population spike, cyclothiazide, hippocampal CA1 neurons

Footnotes

These authors contributed equally to this work.

Contributor Information

Longzhen Cheng, Email: lzcheng@fudan.edu.cn.

Yun Wang, Email: yunwang@fudan.edu.cn.

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