Excitatory GABA, Interneuron Networks, and Epilepsy

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DESCRIPTION (provided by applicant): Brain tissue from patients with intractable temporal lobe epilepsy displays spontaneous epileptiform activity which is dependent upon GABA-mediated transmission. This finding underscores the need for studying synaptic mechanisms of epilepsy in a simple model in which GABAergic transmission is intact. The principal investigator has been studying the 4-aminopyridine model of epilepsy in guinea pig hippocampus, which is a good model for epilepsy occurring in the presence of intact GABAergic transmission. In this model, giant GABAergic postsynaptic potentials (GPSPs), which are caused by interneuron network-mediated synchronous GABA release onto pyramidal cells, directly precede each epileptiform event. The underlying hypothesis is that the depolarizing component of the GPSP is triggering the epileptiform events. It is additionally hypothesized that the epileptiform discharges in pyramidal cells are facilitated because "feedback" interneurons are refractory following the generation of the GPSP. The long-term goal of this study is to identify the functional nature of interneuron-to interneuron synaptic connections in the hippocampus and the role of interneuron networks in the synaptic physiology and pathophysiology of this brain region. This project addresses three important points: 1) Interneuron to interneuron synaptic mechanisms which enable synchronous GABA release in the hippocampus 2) How this synchronous activity in GABAergic neurons facilitates epileptiform activity and 3) How the depolarizing GABA and GABAB components interact to determine whether the synaptically-released GABA is inhibitory or rather is excitatory and proconvulsant. Electrophysiology, along with pharmacological tools, will be used to address these questions. Cell-attached and whole-cell recording from visually-located interneurons will form a key part of the study. The proposed research is innovative because it examines the way in which synchronous activity in GABAergic neurons may work to facilitate epileptiform activity. Understanding the mechanism for epileptiform activity which occurs in the presence of intact GABAergic transmission may lead to the development of new drug therapies for epilepsies which are resistant to currently available drugs; in particular, the experiments may demonstrate the need for development of specific pharmacologic tools targeting excitatory transmission mediated by GABA, or drugs which prevent a reduction in GABAB -mediated transmission.