Evidence That Phospholipase D Activation Prevents Group I mGluR-Induced Persistent Prolongation of Epileptiform Bursts

1 Neural and Behavioral Science Program, School of Graduate Studies and Departments of 2 Neurology and 3 Physiology and Pharmacology, State University of New York Downstate Medical Center, Brooklyn, New York 11203 Submitted 1 December 2003; accepted in final form 16 December 2003 Selective activation of group I metabotropic glutamate receptors (mGluRs) with ( S )-3,5-dihydroxyphenylglycine (DHPG) in guinea pig hippocampal slices converts 275- to 475-ms picrotoxin-induced interictal bursts into persistent seizure-length discharges typically over 1 s in duration. Here we report that L -cysteine sulfinic acid (CSA), a sulfur-containing amino acid, prevented the induction of this persistent group I mGluR-mediated epileptiform burst prolongation. However, CSA had no effect on baseline interictal bursting activity and failed to suppress the expression of the group I mGluR-induced persistent prolonged bursts once they were fully induced. (2 R ,1' S ,2' R ,3' S )-2-(2'-carboxy-3'-phenylcyclopropyl)glycine (PCCG-13), a selective antagonist at the phospholipase D (PLD)-coupled mGluR, had no effect of its own on DHPG-induced burst prolongation; however, CSA applied in the presence of PCCG-13 could no longer fully block the burst prolongation induced by DHPG, suggesting that CSA's antiepileptogenic effect is mediated by agonist action at this PLD-coupled receptor. These data parallel our previous data revealing that protein synthesis inhibitors prevent induction but not expression of group I mGluR-mediated persistent seizure-length discharges. Hence, PLD activation with CSA may prevent the synthesis of a protein critical for the induction of group I mGluR-mediated epileptogenesis. Address for reprint requests and other correspondence: L. R. Merlin, SUNY Downstate Medical Center, 450 Clarkson Ave., Box 29, Brooklyn, NY 11203 (E-mail: lisa.merlin{at}downstate.edu ).