title: Activation of extrasynaptic GABA(A) receptors inhibits cyclothiazide-induced epileptiform activity in hippocampal CA1 neurons.
abstract: Extrasynaptic GABA(A) receptors (GABA(A)Rs)-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(A)Rs 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 GABA(A)R, an extrasynaptic specific GABA(A)R 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 GABA(A)Rs, and further support the hypothesis that tonic inhibition mediated by extrasynaptic GABA(A)Rs plays a prominent role in seizure generation.
authors.affiliation: Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, 200032, China.
authors.forename: Li
authors.initials: L
authors.lastname: Wan
authors.forename: Xu
authors.initials: X
authors.lastname: Liu
authors.forename: Zheng
authors.initials: Z
authors.lastname: Wu
authors.forename: Wanting
authors.initials: W
authors.lastname: Ren
authors.forename: Shuzhen
authors.initials: S
authors.lastname: Kong
authors.forename: Raya Abou
authors.initials: RA
authors.lastname: Dargham
authors.forename: Longzhen
authors.initials: L
authors.lastname: Cheng
authors.forename: Yun
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000818:Animals; D001581:Benzothiadiazines / Q000633:toxicity*; D056547:CA1 Region, Hippocampal / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D003292:Convulsants / Q000633:toxicity*; D004195:Disease Models, Animal; D018755:GABA Agonists / Q000494:pharmacology; D007555:Isoxazoles / Q000494:pharmacology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism / Q000502:physiology*; D012640:Seizures / Q000139:chemically induced / Q000503:physiopathology*
chemical_list: D001581:Benzothiadiazines; D003292:Convulsants; D018755:GABA Agonists; D007555:Isoxazoles; D011963:Receptors, GABA-A; C015542:gaboxadol; C004639:cyclothiazide