Epilepsy has long been considered the result of an imbalance between excitatory and inhibitory activities in the cerebrocortical network. Most studies have focused on the interplay between ionotropic glutamate receptor-mediated excitation and GABA-mediated inhibition. These studies have failed to uncover the basic mechanisms that determine either the frequency or duration of epileptiform discharges. Thus, the processes of ictogenesis (the interictal-to-ictal transition) and epileptogenesis (the induction of epilepsy) have remained elusive. The recent discovery of metabotropic glutamate receptors (mGluRs) has opened a new-avenue of exploration for the study of these phenomena. Our work suggests that activation of these receptors exerts distinct effects on epileptiform activity which are mediated by separate mGluR subclasses. Activation of the mGluR 2 & 3 subclass increases the frequency of preexisting epileptiform bursting, while mGluR 1 & 5 subclass activation elicits prolonged epileptiform bursts suggestive of electrographic ictal activity. Furthermore, the effect of mGluR 2 & 3 activation on epileptiform burst frequency is easily reversed upon washout of the agonist, but the mGluR 1 & 5-induced burst prolongation endures for hours after agonist washout The experiments described in this proposal will examine the mechanisms responsible for these mGluR subclass specific effects on epileptiform activity. Standard electrophysiological and pharmacological techniques will be applied in the guinea pig hippocampal slice to characterize the cellular and transduction mechanisms underlying these two mGluR-mediated effects. Intracellular and extracellular recordings as well as single- electrode voltage clamp recordings will be employed. These studies will further our understanding of the processes underlying epileptogenesis and the interictal-to-ictal transition, and may thereby lead to the development of more effective antiepileptic and anticonvulsant agents.
| Wong, R K; Bianchi, R; Taylor, G W et al. (1999) Role of metabotropic glutamate receptors in epilepsy. Adv Neurol 79:685-98 |
