Abstracts

RATIONALE: Both (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD) and (S)-3,5-dihydroxyphenylglycine (DHPG) convert interictal bursts into ictal-length discharges, suggesting a role for group I metabotropic glutamate receptors (mGluRs) in the interictal-to-ictal transition. However, only DHPG elicits persistent prolongation of epileptiform bursts. While both ACPD and DHPG activate group I mGluRs, there are reported differences in their ability to activate phospholipase D (PLD)-coupled receptors. We therefore examined whether this distinction accounts for the differences in effect of group I mGluR activation via ACPD versus DHPG.
METHODS: Transverse 400 [mu]m guinea pig hippocampal slices were perfused with artificial CSF, oxygenated with 95% O2-5% CO2 and maintained at 35.5-36.0[degree] C. Intracellular recordings were obtained from CA3 stratum pyramidale using thin-walled glass microelectrodes. Drugs were applied via continuous bath perfusion. In all experiments, baseline interictal bursts (350-475 ms) were elicited with picrotoxin, an antagonist of GABAA receptor mediated inhibition (50 [mu]M).
RESULTS: Both ACPD (100 [mu]M, 40 min) and DHPG (50 [mu]M, 40 min) converted picrotoxin-induced interictal bursts into 1.5-2.5 sec discharges (1940 [plusminus] 72 ms, n=5 and 1886 [plusminus] 61 ms, n=6, respectively). ACPD-induced prolonged bursts returned to interictal burst length (461 [plusminus] 23 ms, n=5) within 10 min of agonist washout, while DHPG-induced prolonged bursts persisted for hours following washout (1305 [plusminus] 104 ms at 2 hr washout, n=6). ACPD-induced reversible burst prolongation proceeded unaltered in the presence of L-cysteine sulfinic acid (L-CSA 100 [mu]M), an agonist at PLD-coupled receptors (1761 [plusminus] 27 ms, n=4). In contrast, L-CSA when co-applied with DHPG prevented the induction of prolonged bursts (505 [plusminus] 10 ms, n=7). Nevertheless, maintenance of the prolonged bursts following DHPG washout was not significantly affected by L-CSA application: at one hour washout, burst length was 1007 [plusminus] 32 ms; following 30 min L-CSA, burst length was 1016 [plusminus] 84 ms (n=4).
CONCLUSIONS: Previous work from this laboratory has demonstrated that the selective group I mGluR agonist DHPG elicits persistent burst prolongation, suggesting a role for these receptors in some forms of epileptogenesis. While the induction process appears to be independent of NMDA receptor activation (Galoyan and Merlin 2000) or ongoing bursting activity (Merlin 1999), it is strongly suppressed by protein synthesis inhibitors (Merlin et al, 1998). L-CSA, an agonist at PLD-coupled receptors, has a similar effect to the protein synthesis inhibitors in that it prevents induction of prolonged bursts without suppressing the DHPG-mediated increase in interictal burst frequency. Furthermore, both types of agents have no effect on the maintenance of prolonged bursts once they have been fully induced. These data suggest that L-CSA may be useful as a novel antiepileptogenic agent.
[Supported by: NIH NS40387 to LRM; SFN MNFP to MJR]