This exploratory proposal will investigate a novel hypothesis that extrasynaptic GABAA receptors are sensitive to epileptogenic stimulation and play an important role during epileptogenesis. GABAergic inhibition includes phasic inhibition mediated by fast synaptic GABAergic transmission and tonic inhibition mediated by extrasynaptic GABAA receptors, both of which powerfully regulate neural network excitability. Synaptic GABA transmission and GABAA receptor expression have been demonstrated to be substantially altered in epileptic patients as well as in animal models of epilepsy. However, the functional significance of tonic inhibition during epileptogenesis is not well understood. We have recently established a novel epilepsy model using a chemoconvulsant drug cyclothiazide (CTZ) to induce epileptiform activity in hippocampal neurons both in vitro and in vivo. More importantly, chronic epileptogenic stimulation with CTZ or kainic acid revealed a selective downregulation of tonic GABA currents, suggesting a functional regulation of tonic inhibition during epileptogenesis. This proposal will employ both in vitro and in vivo systems to study tonic inhibition and epileptogenesis: 1) To pinpoint the causal relationship between alteration of tonic inhibition and formation of epileptiform activity in hippocampal cultures. 2) To study functional regulation of tonic inhibition following epileptogenic stimulation of hippocampal slices. 3) To investigate regulation of tonic inhibition in in vivo CTZ epilepsy model. These studies will enhance the understanding of tonic inhibition in information processing of the brain and gain novel insight into the function of extrasynaptic GABAA receptors during epileptogenesis. Potentially, it will facilitate the finding of new antiepileptic treatment. GABAergic inhibition plays a fundamental role in keeping the homeostasis of the brain network activity. Deficits of GABAergic function lead to serious neurological disorders including epilepsy, anxiety, depression, and schizophrenia. This proposal will employ a novel CTZ-induced epilepsy model to investigate functional regulation of tonic inhibition during epileptogenesis both in vitro and in vivo. Understanding functional regulation of tonic inhibition mediated by extrasynaptic GABAA receptors will provide novel insight into the information processing in the brain, and facilitate the finding of new drug target for antiepileptic treatment. ? ? ? ?
