PERINATAL HYPOXIA/ISCHEMIA MODEL OF MR AND EPILEPSY

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Perinatal encephalopathy due to hypoxia/ischemia can result in permanent neurologic deficits such as mental retardation, epilepsy and cerebral palsy. Perinatal hypoxia/ischemia is frequently complicated by acute seizures. The long term goals of this research program are 1) to use animal models to define how the acute seizure activity relates to long term neurobehavioral deficits, and 2) to determine the maturational mechanisms underlying the short and long term epileptogenesis so that age-specific preventative therapies can be devised. In an in vivo rat model of perinatal hypoxia, a striking finding is that hypoxia results in electrographic (EEG) and behavioral seizures in the immature rat, but not in the adult. Rats rendered hypoxic in the perinatal period exhibit increased long term seizure susceptibility. There is no long term effect on seizures after hypoxia at adult ages. The window of development for both the acute and long term epileptogenicity of hypoxia is between postnatal days (P) 5-17 in the rat. To determine if the level of seizure activity during acute hypoxia in the perinatal period affects long term outcome, rats exhibiting varying levels of epileptiform activity during hypoxia will be followed to adulthood. Flurothyl induced seizure susceptibility of these adult rats will be correlated to their behavior during perinatal hypoxia. To identify sites in the brain which are predominantly involved in the generation of hypoxia induced seizures, immunoreactivity to the protein product of an early response gene, c-fos, will be used as a functional map. Relative immunoreactivity in neocortical regions will be compared to that of limbic structures, including the hippocampus, in immature animals sacrificed after hypoxia. Since evidence suggests that the window of development during which hypoxia-induced seizures occur is a period when excitatory mechanisms may predominate over those which are inhibitory, the efficacy of excitatory amino acid (EAA) antagonists will be compared to lorazepam, which is a facilitator of inhibition, for their ability to suppress both the acute hypoxia-induced seizures and the long term consequences. Hippocampal and neocortical brain slices will be studied in vitro after removal from hypoxic immature rats to examine these structures in isolation for evidence of inherent epileptiform activity. These in vitro experiments allow the study of individual brain regions, which is not possible in vivo, where afferent connectivity may alter spontaneous and evoked neuronal activity. Animals will be treated with drugs in vivo prior to hypoxia, and slices will be removed after hypoxia to determine if in vitro activity reveals specific regional correlates to in vivo drug efficacy. The overall goal is to use these in vivo and in vitro model systems together to identify maturational factors responsible for the unique responses observed in the whole animal so that. their underlying Molecular, physiological, and biochemical mechanisms may be studied.