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

Extrasynaptic GABA_A receptors(GABA_ARs)-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 GABA_ARs 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 umol/L)significantly reduced the multiple PS peaks induced by CTZ stimulation.Western blot showed that the 5-subunit of the GABA_AR,an extrasynaptic specific GABA_AR subunit,was also significantly down-regulated in the cell membrane 2h after CTZ treatment.Our results suggest that the CTZ-induced epileptiform activity in hippocampal CA1neurons is suppressed by the activation of extrasynaptic GABA_ARs,and further support the hypothesis that tonic inhibition mediated by extrasynaptic GABA_ARs plays a prominent role in seizure generation.