Decreased time constant in hippocampal dentate granule cells in pilocarpine-treated rats with progressive seizure frequencies.

Glutamate-mediated excitotoxic cell damage has been implicated in epilepsy. Although evidence accumulates for prolonged acute seizures resulting in unequivocal cell damage, whether excitotoxicity is involved in spontaneous seizures in chronic epilepsy is poorly understood. In the present study, a frequency of spontaneous seizures, independent of exogenously applied stimulus, was studied in relation to hippocampal hyperexcitability in the pilocarpine model. A long-term observation (12 h/day for 120 or 280 days) of spontaneous seizures identified an average basic seizure frequency of 0.11 seizures/day +/- 0.03 S.E.M. in 30 animals. However, in 1/3 of these animals (n = 9), a seizure frequency significantly increased to 2.57 seizures/day +/- 0.25 S.E.M. (ranging from 2-13 seizures/day) in 40-165 days, and this period of high frequency of seizures lasted for 20-95 days. Hippocampal slices were prepared at the end of the observation period for extracellular field responses and whole-cell patch clamp recordings. In slices that were prepared from rats that showed progressive frequencies of seizures, glutamate-mediated excitatory postsynaptic responses were prolonged in hippocampal dentate granule cells (DGCs) from which multiple spikes were generated in higher probability. Average time constant was shorter in these cells (14.2 ms +/- 2.1 S.E.M., P < 0.01) compared with normal DGCs in control animals (21.2 ms +/- 3.7 S.E.M.) suggesting that cell structural diminution possibly occurred during the recurrence of spontaneous seizures. It is suggested that on-going seizure activities could progress in frequency during the recurrence of spontaneous seizures and neuronal degeneration might be accompanied with increasing frequencies of spontaneous seizures that were mediated by the increased activation of glutamate receptors.