The overall objective of this proposal is to elucidate the metabotropic glutamate receptor (mGluR)-mediated conductances underlying the rhythmic, prolonged synchronized bursts elicited in the hippocampus via mGluR agonist application. The generation of the prolonged synchronized bursts is complex, involving the interaction between the ionotropic glutamate receptor (iGluR)- and mGluR-mediated conductances. While the properties of the iGluR-mediated conductances are well characterized, information on the mGluR-mediated conductances and their respective contribution to synaptic responses is extremely limited. To provide the necessary background information, the applicant will first characterize the mGluR-mediated conductances activated under two simpler, more controllable experimental conditions. Specifically, the mGluR-dependent conductances elicited by agonist application and synaptic activation will be characterized in the presence of iGluR antagonists. The contribution of each conductance to the synchronized bursts will then be elucidated. Finally, according to the applicant's recent data, transient exposure of hippocampal slices to mGluR agonists produces long-lasting changes in the neuronal population so that prolonged synchronized discharges persist for hours after agonist washout. The mGluR-mediated conductances underlying this persistent change in population behavior will also be explored. Intracellular sharp-electrode and whole-cell recordings will be carried out. Changes in intracellular Ca2+ concentration during the course of mGluR responses will be explored using the whole-cell imaging with Ca2+-sensitive fluorescent dyes. The applicant will evaluate the Ca2+ dependency of the mGluR-mediated conductances and the possible involvement of Ca2+ as a signal transduction step in their activation. To the extent that a prolonged synchronized discharge is the cellular event underlying seizure and ictal discharges, the results of the study are expected to contribute to an understanding of the generation of hypersynchronized discharges which are associated with epilepsy.
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