Abstracts

Rationale: Hippocampal dentate granule cells (DGCs) function as a buffer against seizure propagation through the limbic circuit. Studies in animal models of epilepsy suggest that entorhinal cortical seizures reach the hippocampus only if they activate DGCs synchronously. Synchronous activation of DGCs is normally kept in check by powerful inhibitory innervation of these cells. Therefore, a major research focus is to determine how inhibitory input to DGCs changes during epileptogenesisMethods: Rats were subjected to pilocarpine (PILO) treatment to induce status epilepticus, which was terminated after 1 hr by diazepam. This induced the subsequent emergence of spontaneous seizures 2-4 weeks post treatment. Patch-clamp techniques were used to examine several aspects of DGC inhibition, including spontaneous and miniature postsynaptic currents (sIPSCs and mIPSCs), as well as tonic GABA-mediated currents due to activation of extrasynaptic GABAA receptors by ambient GABA in latent period (4-14 days post PILO) and chronically epileptic animals (>3 month post PILO). Results: All measures of DGC inhibition (s- and mIPSCs, as well as tonic currents) were decreased in animals 4-14 days after PILO treatment, during the latent period prior to the onset of spontaneous seizures. Paradoxically, all of these inhibitory efficacy measures were increased 3 months post PILO, in chronically epileptic animals. Conclusions: Our results suggest that reduced inhibitory input to DGCs may underlie the initial period of epileptogenesis, and that hyperexcitability during chronic epilepsy may involve other mechanisms.