Abstracts

Rationale: We documented previously that chronic treatment with Ro25-6981 (Ro; 1 M) attenuated susceptibility to seizures induced by bicuculline (BMI) in hippocampal cultures as shown by decreased seizure duration and number (Wang & Bausch, 2004). This effect persisted for at least 24 hr after Ro removal and was accompanied by reduced neuronal death and mossy fiber sprouting. In contrast, chronic treatment with D-APV (50 M) exacerbated BMI-induced seizure susceptibility, neuronal death, and mossy fibers sprouting. In this study, we examined the concentration dependence of Ro and APV effects on susceptibility to seizures induced by BMI or removal of Mg2 from the recording buffer. Methods: Hippocampal slices obtained from P11 S/D rats were cultured for 17 to 21 days in media containing increasing concentrations of Ro or APV. Drugs were omitted from media for controls. After chronic treatment, slices cultures were superfused with artificial cerebrospinal fluid (aCSF, 32-34C) for 30min to remove drugs. Field potentials were recorded from the suprapyramidal blade of the dentate granule cell layer for 45min. Seizures were induced either by perfusion with aCSF without Mg2 (0Mg2 ) to increase glutamatergic excitation or by aCSF containing BMI (10 M) to suppress GABAergic inhibition. Results: As expected, BMI-induced seizures were suppressed following chronic treatment with Ro in a concentration dependent manner. At 1 M, Ro significantly (p<0.05) decreased total seizure duration and number by 72% and 58%, respectively and increased the latency to first seizure by 95%. Interestingly, 0Mg2 -induced seizures displayed a biphasic concentration-response curve following chronic treatment with Ro. At 1nM, Ro significantly increased total seizure duration and number by 55% and 60%, respectively and reduced the latency to first seizure by 12%. At 1 M, Ro significantly decreased total seizure duration and number by 65% and 57%, respectively and increased the latency to first seizure by 22%. In contrast, both BMI- and 0Mg2 -induced seizures were exacerbated in a concentration-dependent manner following chronic treatment with APV. At 50 M, APV significantly: 1) increased total seizure duration by 266%, 0Mg2 , 60%, BMI; 2) increased seizure number by 106%, 0Mg2 , 74%, BMI; and 3) reduced the latency to first seizure by 53%, 0Mg2 , 39%, BMI. Conclusions: These data show that chronic treatment with Ro and APV exerted opposite, concentration-dependent effects on seizure expression. The exception was the potential epileptogenic effect of 1nM Ro for 0Mg2 -induced seizures, which may be attributed to a differential selectivity of Ro for bi- versus triheteromeric NMDAR in GABAergic interneurons.