Epileptic seizures induced by N-acetyl-L-aspartate in rats: in vivo and invitro studies

Tremor rat (tm/tm), the parent strain of spontaneously epileptic rat (SER: zi/zi, tm/tm), exhibits absence-like seizures characterized by 5-7 Hz spike -wave-like complexes on cortical and hippocampal electroencephalograms (EEG ) after 10 weeks of age, prior to development of convulsive seizures. Recen tly, this animal model has been demonstrated to display a genomic microdele tion within the critical region of an, where aspartoacylase hydrolyzing N-a cetyl-L aspartate (NAA) is located, besides showing the ability to accumula te NAA in the brain. Therefore, the present study was performed to determin e the involvement of NAA in the induction of epileptic seizures. When NAA ( 4 mu mol) was applied intracerebroventricularly (i.c.v.) to normal Wistar r ats, 4-10 Hz polyspikes and/or spike-wave-like complexes followed by absenc e-like seizure before persistent 1-5 Hz waxing high-voltage after-discharge s were observed on cortical and hippocampal EEG. At a higher dose (8 mu mol ), NAA induced convulsive seizures. The absence-like seizures with polyspik es and/or spike-wave-like complexes on the EEG were also observed with i.c. v. NAA in premature tremor rats without seizures. The NAA-induced seizures in normal rats were antagonized by i.c.v. glutamic acid diethyl ester, a no n-selective glutamate receptor antagonist. In addition, NAA applied to the bath rapidly induced a :long-lasting depolarization concomitantly with repe titive firings in hippocampal CA3 neurons of normal rat brain slice prepara tions. These findings suggest that NAA is involved in the induction of abse nce-like seizures and/or convulsion, probably via glutamate receptors. (C) 2000 Elsevier Science B.V. All rights reserved.