Group I metabotropic glutamate receptor (mGluR) agonists elicit seizures in vivo, and antagonists are effective anticonvulsants. My work in the in vitro hippocampus has begun to elucidate the mechanisms for this group I mGluRmediated convulsant effect. My data not only reveal that group I mGIuR activation converts brief synchronized interictal discharges into prolonged seizure-length events, but also demonstrate that the prolonged mGluR-induced epileptiform discharges persist long after agonist washout, additionally suggesting a heretofore-unsuspected role for group I mGluRs in epileptogenesis (the induction of a persistent seizure-prone state). Furthermore, the persistent prolonged discharges are sustained by an ongoing group I mGluR-linked process, as they are reversibly suppressed by group I mGluR antagonists. Thus, transient activation of group I mGluRs appears to elicit a long-term enhancement of a group. mGluR-linked excitatory process which helps sustain the persistent production of seizure-like discharges. The primary aims of this proposal are to identify the physiological processes underlying these group I mGluR-mediated long-lasting excitatory effects and to evaluate their physiological relevance.
Specific Aim I will begin to examine the mechanism by which group I mGluR activation elicits epileptiform burst prolongation by first studying possible postsynaptic long-lasting modifications; electronic coupling and glial cell involvement will be considered as well. Cellular processes that promote or prevent the persistence of the group I mGluR-mediated epileptiform activity will be investigated in Specific Aim II. And, finally, the in vitro kindling model will be used in Specific Aim III to explore the relevance of these group I mGluR-mediated effects to the physiological processes underlying seizure initiation and epileptogenesis. A combination of electrophysiological and pharmacological techniques will be used in guinea pig hippocampal slices to characterize the cellular and synaptic mechanisms for the long-lasting group I mGluR-mediated network modification. Intracellular recordings from CA3 pyramidal cells will be performed, and subgroup-specific mGluR agonists and antagonists will be applied. These studies should elucidate triggering mechanisms underlying seizures and epilepsy, thereby aiding in the development of more selective or specifically-targeted antiepileptic and anticonvulsant agents with higher efficacy and fewer side effects than the agents currently available.
