CONTRASTING ROLES OF PROTEIN KINASE C IN INDUCTION vs. SUPPRESSION OF GROUP I mGluR-MEDIATED EPILEPTOGENESIS IN VITRO

Activation of group I metabotropic glutamate receptors (mGluRs) elicits persistent ictaform discharges in guinea pig hippocampal slices, providing an in vitro model of epileptogenesis (Merlin and Wong 1997). The induction of these persistent ictaform bursts is prevented by Lcysteine sulfinic acid (CSA), an agonist at phospholipase D (PLD)-coupled mGluRs (Rico and Merlin 2004). Studies described herein examined the role of protein kinase C (PKC) in both the group I mGluR-mediated induction and CSA-mediated suppression of this form of epileptogenesis. Intracellular recordings were performed from CA3 stratum pyramidale and synchronized burst length was monitored. In the presence of 50 μM picrotoxin, a GABAA antagonist, 250-500 ms synchronized bursts were elicited. (S)-3,5-dihydroxyphenylglycine (DHPG, 50 μM), an agonist at group I mGluRs, increased the burst length to 1-3 sec in duration, a change that persisted following agonist washout. This persistent change in burst length was elicited in the presence of 10 μM chelerythrine, a PKC inhibitor, indicating that DHPG-induced epileptogenesis is PKC independent. However, while PLD activation with CSA (100 μM) was highly effective at suppressing group I mGluR-mediated induction of burst prolongation, CSA application in the presence of chelerythrine was no longer effective and resulted in the expression of persistent ictaform bursts. These data suggest that CSA-mediated suppression of group I mGluR-induced epileptogenesis is PKC dependent. We propose that CSA mediates its effect via PLD-driven activation of PKC, which may desensitize the phospholipase C-linked group I mGluRs and thereby prevent group I mGluR-induced epileptogenesis.