Timing of cognitive deficits following neonatal seizures: relationship to histological changes in the hippocampus

Neonatal seizures are frequently associated with cognitive impairment and r educed seizure threshold. Previous studies in our laboratory have demonstra ted that rats with recurrent neonatal seizures have impaired learning, lowe r seizure thresholds, and sprouting of mossy fibers in CA3 and the supragra nular region of the dentate gyrus in the hippocampus when studied as adults . The goal of this study was to determine the age of onset of cognitive dys function and alterations in seizure susceptibility in rats subjected to rec urrent neonatal seizures and the relation of this cognitive impairment to m ossy fiber sprouting and expression of glutamate receptors. Starting at pos tnatal day (P) 0, rats were exposed to 45 flurothyl-induced seizures over a 9-day period of time. Visual-spatial learning in the water maze and seizur e susceptibility were assessed in subsets of the rats at P20 or P35. Brains were evaluated for cell loss, mossy fiber distribution, and AMPA (GluR1) a nd NMDA (NMDAR1) subreceptor expression at these same time points. Rats wit h neonatal seizures showed significant impairment in the performance of the water maze and increased seizure susceptibility at both P20 and P35. Sprou ting of mossy fibers into the CA3 and supragranular region of the dentate g yrus was seen at both P20 and P35. GluR1 expression was increased in CA3 at P20 and NMDAR1 was increased in expression in CA3 and the supragranular re gion of the dentate gyrus at P35. Our findings indicate that altered seizur e susceptibility and cognitive impairment occurs prior to weaning following a series of neonatal seizures. Furthermore, these alterations in cognition and seizure susceptibility are paralleled by sprouting of mossy fibers and increased expression of glutamate receptors. To be effective, our results suggest that strategies to alter the adverse outcome following neonatal sei zures will have to be initiated during, or shortly following, the seizures. (C) 2001 Published by Elsevier Science B.V.