Neonatal
seizures are frequently associated with
cognitive impairment and reduced seizure threshold. Previous studies in our laboratory have demonstrated that rats with recurrent neonatal
seizures have impaired learning, lower seizure thresholds, and sprouting of mossy fibers in CA3 and the supragranular 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 dysfunction and alterations in seizure susceptibility in rats subjected to recurrent neonatal
seizures and the relation of this
cognitive impairment to mossy fiber sprouting and expression of
glutamate receptors. Starting at postnatal 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 seizure susceptibility were assessed in subsets of the rats at P20 or P35. Brains were evaluated for cell loss, mossy fiber distribution, and
AMPA (GluR1) and
NMDA (
NMDAR1) subreceptor expression at these same time points. Rats with neonatal
seizures showed significant impairment in the performance of the water maze and increased seizure susceptibility at both P20 and P35. Sprouting of mossy fibers into the CA3 and supragranular region of the dentate gyrus 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 region of the dentate gyrus at P35. Our findings indicate that altered seizure 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
seizures will have to be initiated during, or shortly following, the
seizures.