The transient activation of group I metabotropic glutamate receptors (group I mGluRs) by an agonist induces epileptiform discharges in hippocampal slices. These discharges persist for hours after the washout of the agonist. This action of group I mGluR - transforming a 'normal' hippocampal slice into an 'epileptic-like' one - may represent a form of epileptogenesis. At present, the cellular processes underlying this model of epileptogcnesis is unknown. We hypothesize that one plastic change induced by a transient stimulation of group I mGluRs is the persistent activation of an ionic current, ImGluR(V). We first described ImGluuR(V ) as a voltage-dependent cationic current activated by group I mGluR stimulation. We have also showed that ImGluR(V) activation is necessary for the generation of the mGluR-mediated epileptiform discharges. We now propose that ImGluR(V), once induced, will be persistently active to sustain the long lasting epileptiform discharges. The focus of this application is to assess the validity of this hypothesis. There are three specific aims. We will: (1) define the duration and strength of group ImGluR stimulation necessary to induce ImGluR(V) responses in CA3 pyramidal cells, (2) explore the plasticity mechanisms underlying in the induction of ImGluR(V) and (3) examine the signaling mechanisms involved in the maintenance of ImGluR(V). ImGluR(V) responses in CA3 pyramidal cells will be monitored by voltage-clamp experiments using sharp and patch electrodes. In addition, the plasticity and signaling processes underlying the induction and maintenance of ImGluR(v) will be examined using pharmacological and biochemical approaches and electrophysiological recordings. Since ImGluR(V) has been shown to play a necessary role in the generation of mGluR-mediated synchronized discharges and its induction may constitute an essential cellular process for the maintenance of long lasting epileptiform discharges, we expect the results of the proposed study on the properties of ImGluR(v) to yield useful linformation on the basic mechanisms of epileptogenesis.
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