Mediation of cyclothiazide induced epileptiform activity in hippocampal neurons by extrasynaptic GABAA receptors
演題番号 : P3-n26
Yajie Sun:1 Shuzhen Kong:1,2 Gong Chen:3 Yun Wang:1,2
1:Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China 2:Research Centre of Medicinal Chemistry and Chemical Biology, Chongqing Technology and Business University, Chongqing, China 3:Department of Biology, Huck Institutes of Life Sciences, Pennsylvania State University, University Park, USA
Previous work from our laboratories has shown that cyclothiazide (CTZ) induces seizure behavior in freely moving rats (Kong et al., 2007) and epileptiform activity in hippocampal neurons, which is accompanied by a selective downregulation of extrasynaptic GABAA receptors (Qi et al., 2006a, 2006b). We further studied whether downregulation of extrasynaptic GABAA receptor mediated tonic inhibition is important to the formation of this epileptiform activity, by using a selective extrasynaptic GABAA receptor agonist THIP (Gaboxadol) and extrasynaptic GABAA receptor overexpression. In hippocampal culture, chronic treatment of hippocampal cultures with CTZ induces epileptiform activity in ~80% of neurons. After simultaneous chronic treatment of cultures with CTZ and THIP, the percentage of neurons showing epileptiform activity was reduced to ~40%. Meanwhile, our preliminary data indicated that CTZ induced bursting was reduced in neurons transfected with α6/β3/δ subunits of GABAA receptor.In anaesthetized rats, CTZ dose-dependently (1 and 5 micromol i.c.v. at 5 microlitre), induced epileptiform activity characterized by progressing of multiple population spike peaks, spontaneous spiking, and synchronized epileptiform bursts. When the stable synchronized epileptiform bursts established, low doses of THIP (2 and 4 mg/kg) was administrated intravenously, which reversibly inhibited CTZ induced bursting activity in majority of the rats tested.In conclusion, our results demonstrate that enhancement of the activity of extrasynaptic GABAA receptors significantly decrease the robustness of previously established epileptiform activity which suggest that extrasynaptic GABAA receptors might be a prominent drug target for anticonvulsant.