SUPPRESSION BY TOPIRAMATE OF EPILEPTIFORM BURST DISCHARGES IN HIPPOCAMPAL CA3 NEURONS OF SPONTANEOUSLY EPILEPTIC RAT IN-VITRO

Topiramate, a novel antiepileptic drug, inhibits the seizures of spont aneously epileptic rat (SER), a double mutant (zi/zi, tm/tm) which exh ibits both tonic convulsion and absence-like seizures from the age of 8-weeks. Hippocampal CA3 pyramidal neurons in SER show a long-lasting depolarization shift with accompanying repetitive firing when a single electrostimulation is delivered to the mossy fibers in vitro. The eff ects of topiramate on the excitability of CA3 pyramidal neurons in SER were examined to elucidate the mechanism underlying the antiepileptic action. Intracellular recordings were performed in 23 hippocampal sli ce preparations of 16 SER aged 8-17 weeks. Topiramate (10-100 mu M) do se-dependently inhibited the depolarizing shifts with repetitive firin g induced by mossy fiber stimulation without affecting the first spike and resting membrane potentials in hippocampal CA3 neurons of SER. Hi gher dose of topiramate (100 mu M) sometimes inhibited the first spike , and decreased excitatory postsynaptic potentials in the SER CA3 neur ons. However, topiramate up to 100 mu M did not affect the single acti on potential elicited by the stimulation in the hippocampal CA3 neuron s of age-matched Wistar rat devoid of the seizure. Application of topi ramate (100 mu M) did not significantly affect the firing induced by d epolarizing pulse applied in the CA3 neurons of the SER. In addition, topiramate (100 mu M) had no effects on the Ca2+ spike induced by intr acellularly applied depolarizing pulse in the presence of tetrodotoxin and tetraethylammonium. In contrast, a dose-dependent inhibition of d epolarization and repetitive firing induced by bath application of glu tamate in CA3 pyramidal neurons was obtained with topiramate (10-100 m u M) Furthermore, topiramate (100 mu M) decreased the number of miniat ure postsynaptic potential of CA3 pyramidal neurons of SER. In patch c lamp whole cell recording using acutely dissociated hippocampal CA3 ne urons from SER aged 8-weeks and age-matched normal Wistar rats, there were no remarkable effects on voltage dependent Ca2+ current with topi ramate up to 300 mu M in either animal; the current was completely blo cked by Cd2+ at a concentration of 1 mM. These findings suggest that t opiramate inhibits release of glutamate from the nerve terminals and/o r abnormal firing of the CA3 pyramidal neurons of SER by mainly blocki ng glutamate receptors in the neurons. (C) 1998 Elsevier Science B.V.