Abstracts

RATIONALE: I have previously demonstrated that selective activation of group I metabotropic glutamate receptors (mGluRs) with DHPG has two effects on in vitro interictal activity in the CA3 region: a rapid-onset increase in burst frequency, and a slowly-progressive and long-lasting increase in burst duration. As DHPG activates both mGluR1 and mGluR5 (the two subtypes belonging to group I), and both receptor subtypes are present in the CA3 region, experiments were designed to determine which receptor subtypes are responsible for the DHPG-induced epileptogenic effects. METHODS: Interictal bursts were induced in guinea pig hippocampal slices by bath application of 50 M picrotoxin. In the presence of agents that block either mGluR1 or mGluR5, (S)DHPG (25-50 M) was introduced and the resultant activity was recorded from CA3 pyramidal cells with intracellular electrodes. RESULTS: The mGluR5 antagonist MPEP (100 M) slowed the frequency of interictal bursts without affecting burst duration (n=3), and the mGluR5 agonist CHPG (1 mM) increased interictal burst frequency (n=5) but increased burst duration in only 1 of 5 slices. Neither the mGluR1 antagonist LY367385 (20 M, n=3) nor the mGluR5 antagonist MPEP (n=3) prevented the DHPG-induced increase in interictal burst frequency, but they each independently suppressed the ability of DHPG to elicit an increase in burst duration. CONCLUSIONS: The results suggest that activation of either mGluR1 or mGluR5 can independently elicit an increase in interictal burst frequency, and mGluR5 activation by synaptically-released glutamate contributes to determining interictal burst frequency. The data also suggest that the induction of the group I mGluR-mediated burst prolongation may require concurrent activation of both mGluR1 and mGluR5 since blocking either one suppresses DHPG's ability to elicit this response. As I have previously shown that autopotentiation of group I mGluR responses underlies the maintenance of the group I mGluR-mediated burst prolongation, further experiments are necessary to determine which receptor subtypes express the autopotentiation which maintains the group I-mediated epileptogenesis.