Compromised GABA Recycling as an Epileptogenic Mechanism

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Temporal lobe epilepsy (TLE) is the most common epileptic syndrome in adults, and also the most intractable. It is a symptomatic condition, i.e. one associated with a prior insult. The processes involved in generation of pathological, epileptiogenic alterations following brain injury are largely unknown. We provide evidence that GABA recycling mechanisms are compromised in inhibitory synapses in the brains of animals with TLE. GABA recycling is required to reload synaptic vesicles following release, a critical function determining the ability of inhibitory synapses to dynamically regulate circuit excitability in active areas of brain. Studies in the present proposal are designed to specifically test our CENTRAL HYPOTHESIS: Compromise in GABA recycling mechanisms is a pivotal, early event in epileptogenesis. Furthermore, restoration of normal GABA production early following an epileptogenic injury will be a viable therapeutic intervention, capable of blunting the severity of or curing the subsequent development of epilepsy. Research directed at testing our central hypothesis will focus on 4 SPECIFIC AIMS: AIM 1: Determine the predominant mechanisms mediating GABA production and recycling in hippocampal inhibitory synapses of chronically epileptic animals. AIM 2: Determine the time course of onset of altered GABA recycling mechanisms during epileptogenesis. AIM 3: Determine the functional consequences of alternate GABA recycling mechanisms in regulating excitability of the hippocampus in epileptic animals, and assess mechanisms to restore glutamine-glutamate cycle function. AIM 4: Determine strategies to either restore glutamine-glutamate cycle function, or enhance the capacity of GABAergic synapses to produce GABA by alternate mechanisms in animals which are in the process of developing epilepsy. Using a combination of electrophysiological, molecular, and whole animal approaches, the present proposal will elucidate how changes in metabolic processes within inhibitory synapses compromise inhibitory efficacy and predispose the hippocampus to seizure generation in TLE. Furthermore, we will determine how early interventions in these pathophysiologic processes may alter disease progression. Understanding the nature of epileptogenic changes at the functional, molecular, and whole animal level is an absolute prerequisite to facilitate the development of new therapeutic strategies to better treat and perhaps cure this devastating disorder.