Abstracts

Activation of group I metabotropic glutamate receptors (mGluRs) by dihyroxyphenylglycine (DHPG) results in long-lasting changes in hippocampal physiology that includes spontaneously occurring epileptiform discharges. In this study we assess the role of calcium influx on the induction of epileptiform activity by DHPG. Hippocampal slices were prepared from young male Sprague-Dawley rats (30-40 day old). Control slices were incubated in oxygenated artificial cerebrospinal fluid (ACSF) and racemic DHPG (100 [mu]M) for 60-120 min before being transferred to an interface recording chamber. Slices were also incubated in the presence of DHPG and EGTA (500 [mu]M), the L-type calcium channel blocker diltiazem (30 [mu]M), or the transient receptor potential channel (TRPC) blocker SKF 96365 (30 [mu]M). Once transferred, slices were bathed in control ACSF for 1 hr before extracellular recordings were made in the CA3 region to assess for spontaneously occurring epileptiform activity. Activity was characterized as interictal if less than 500 ms duration or ictal if [gt]2 s. Control DHPG-exposed slice activity was compared to the activity in slices incubated with DHPG and a drug that interfered with calcium influx. EGTA buffering resulted in only 5% of slices displaying interictal activity (n = 20) compared to control DHPG-exposed slices that resulted in 32% with ictal and 32% with interictal patterns (n = 22). Incubation in the presence of the L-type calcium channel blocker diltiazem reduced the number of slices displaying epileptiform activity compared to DHPG-exposed slices alone (30% vs. 83% of slices, n = 46 and 42). The TRPC blocker SKF 96365 suppressed the induction of epileptiform activity in all 32 slices exposed to DHPG with control DHPG-exposed slices demonstrating spontaneously occurring epileptiform activity in 59% (n = 34). A statistically significant reduction in the induction of epileptiform activity occurred when extracellular calcium influx was inhibited compared to control DHPG-exposed slices (Chi-square, p [lt] 0.05). Calcium influx from the extracellular space promoted the induction of epileptiform activity by group I mGluR exposure. Influx from either the L-type calcium channel or TRP channels contributed to the induction of epileptiform activity by group I mGluRs. Recent evidence supports TRPC1 activation by group I mGluRs and our results suggest that calcium influx through a TRP channel contributes to the induction of long term changes in excitability produced by group I mGluR activation. (Supported by VA Research)