Enhancement of progenitor cell division in the dentate gyrus triggered by initial limbic seizures in rat models of epilepsy

Purpose: Mitogenic effects of seizures on granule cell progenitors in the d entate gyrus were studied in two rat models of epilepsy. We investigated wh ich stage of epileptogenesis is critical for eliciting progenitor cell divi sion and whether seizure-induced neuronal degeneration is responsible for t he enhancement of progenitor cell division. Methods: Seizures were induced by either kainic acid (KA) administration or electrical kindling. Neurogenesis of dentate granule cells was evaluated u sing the bromodeoxyuridine (BrdU) labeling method, and neuronal degeneratio n was assessed by in situ DNA fragmentation analysis. Results: After injection of KA, the number of BrdU-positive granule cells b egan to increase at day 3 after the treatment, peaked at day 5, and returne d to baseline at day 10. By day 13, the values were lower than control. Aft er kindling, the number of BrdU-positive cells began to increase after five consecutive experiences of stage I seizures. The increase occurred from da y 1 to day 3 after the last electrical stimulation, but returned to baselin e by day 7. After generalized seizures were well established, repeated stim ulation did not facilitate division of granule cell progenitors. DNA fragme ntation was noted in pyramidal neurons in the CA1, CA3, and hilus regions a t 18 h after KA injection, but not in the kindling model. Conclusions: These observations indicate that a mechanism in epileptogenesi s boosts dentate progenitor cell division, but progenitor cells may become unreactive to prolonged generalized seizures. Pyramidal neuronal degenerati on is not necessary for triggering the upregulation. II is suggested that n ewly born granule cells may play a role in the network reorganization that occurs during epileptogenesis.