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

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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.

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Authors and Affiliations

  1. Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, 200032, China

    Li Wan, Zheng Wu, Wanting Ren, Shuzhen Kong, Raya Abou Dargham, Longzhen Cheng & Yun Wang

  2. Neurology Department, Zhongshan Hospital, Fudan University, Shanghai, 200032, China

    Xu Liu

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  1. Li Wan
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Correspondence to Longzhen Cheng or Yun Wang.

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Wan, L., Liu, X., Wu, Z. et al. Activation of extrasynaptic GABAA receptors inhibits cyclothiazide-induced epileptiform activity in hippocampal CA1 neurons. Neurosci. Bull. 30, 866–876 (2014). https://doi.org/10.1007/s12264-014-1466-8

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  • DOI: https://doi.org/10.1007/s12264-014-1466-8

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