Abstracts

RATIONALE: I have previously shown that selective activation of group I metabotropic glutamate receptors (mGluRs) converts interictal bursts into persistent prolonged synchronized discharges. The prolonged discharges are suggestive of ictal events; their persistance implicates an epileptogenic process. Both mGluR1 and mGluR5, the two subtypes belonging to group I, participate in the induction of the burst prolongation (Merlin, Epilepsia 41: 18-19, 2000), and the maintenance of the burst prolongation is sustained by continued activation of group I mGluRs by endogenous glutamate (Merlin & Wong, J. Neurophysiol. 78: 539-544, 1997; Merlin, J. Neurophysiol. 1078-1081, 1999). Experiments were designed to determine the relative roles of mGluR1 and mGluR5 in the maintenance of the burst prolongation.
METHODS: Interictal bursts were induced in guinea pig hippocampal slices by bath application of 50 [mu]M picrotoxin, an antagonist of GABAa receptor-mediated inhibition. Application of the selective group I mGluR agonist (S) 3,5-dihydroxyphenylglycine (DHPG, 50 [mu]M) for 30-40 min resulted in persistent prolongation of the interictal bursts. Selective antagonist for either mGluR1 or mGluR5 was introduced after at least one hour washout of DHPG. Intracellular recordings from CA3 pyramidal cells were used to monitor the results.
RESULTS: The mGluR1a antagonist (S)-(+)-[alpha]-amino-4-carboxy-2-methylbenzeneacetic acid (LY367385, 20 [mu]M) returned the persistent prolonged bursts to their control length before DHPG exposure, reducing their length from 1469 [plusminus] 134 ms to 508 [plusminus] 110 ms (n=4). In contrast, the mGluR5 antagonist 1-methyl-6-(phenylethynyl)pyridine (MPEP hydrochloride, 25 [mu]M) only partially suppressed the prolonged discharges, reducing their length from 1712 [plusminus] 233 ms to 889 [plusminus] 148 ms (n=4).
CONCLUSIONS: The data suggest that both mGluR1 and mGluR5 participate in the maintenance of the group I mGluR-induced prolongation of epileptiform discharges. However, mGluR1 appears to play a more significant role, as antagonism of this receptor subtype alone is sufficient to completely suppress the burst prolongation. This therefore suggests that selective antagonism of mGluR1 may be sufficient to suppress ictal discharges, and agents with this mechanism of action may therefore serve as useful anticonvulsants with fewer side effects than the currently available agents.
Support: National Institutes of Health (NINDS) grants NS01901 and NS40387