Newborns are at high risk for seizures and seizure-associated brain injury. Between 20-40 percent of term infants who have seizures are subsequently handicapped and this increases to almost 90 percent in pre-term babies. Despite the clinical importance of this problem, little is known about the pathophysiological basis of seizure-induced brain damage in newborns. The goals of this proposal are to delineate the neurobiological consequences of neonatal seizures. ? ? We have demonstrated that neonatal seizures, while not causing cell loss, result in changes in synaptic organization with sprouting of mossy fibers in the CA3 and supragranular regions, reductions in neurogenesis, and impairment in spatial memory. We hypothesize that neonatal seizures perturb the development of the hippocampal network by disrupting normal excitatory and inhibitory synapse development resulting in permanent alterations in hippocampal neuronal circuits and hippocampal network patterned activities. Furthermore, these alterations in hippocampal network properties result in functional impairment. To assess this hypothesis, we will employ ex vivo and in vivo electrophysiological techniques and behavioral studies in three specific aims. In the first aim we hypothesize that seizures in the neonatal period result in alterations in neuronal circuitry with subsequent decreases of place firing field precision and stability and abnormal hippocampal rhythms and patterns. Further, we hypothesize that these abnormalities will be associated with abnormalities in visual-spatial memory. We will assess place cell firing patterns and hippocampal network activity in animals with and without a history of neonatal seizures and compare these findings to performance in the water maze. We also hypothesize that neonatal seizures result in alterations in hippocampal patterned activity.
Our second aim complements the first aim by determining the persistence of changes in network activity after neonatal seizures by monitoring hippocampal rhythms and patterns throughout development. Our third specific aim is to determine the effects of neonatal seizures on developmental changes in synaptic connections that can underlie the alterations in ontogenesis of hippocampal network activity described in aim 2 and the long-term effects of neonatal seizures on cognition and place cell physiology described in aim 1. These integrated aims will provide insight into the mechanisms of seizure-induced injury in newborns and form the basis for subsequent therapeutic interventions.
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