This project will study excitotoxic mechanisms of brain damage induced by seizures in the brain of the neonate. We will develop a model of repetitive seizures induced by N-methyl-D-aspartate (NMDA) in ten-day-old rats. Blood pressure, blood gases and other physiological parameters will be monitored and corrected in order to ascertain whether the resulting brain damage is associated with the seizures themselves or their systemic complications. We will describe and quantify the degree of brain damage with emphasis on the hippocampus, will establish dose and time curves, and the age dependence of seizure-induced damage. We expect to find a distribution of damage in the inner layer granule cells. The excitotoxic nature of the lesions will be confirmed by electron microscopy, by treatment with blockers of the NMDA receptor, and by entorhinal lesions. We will also develop a model of excitotoxic brain damage in immature rats by stimulation of the perforant path. We expect that the resulting release of endogenous glutamate will damage the inner layer granule cells of the dentate gyrus and that this will be blocked by NMDA antagonists. We also expect that less vigorous stimulation which does not cause neuronal necrosis will inhibit hippocampal growth. This will be studied with specific markers for astrocytes, myelin, and various neuronal subpopula- tions. The key findings obtained in rodents will be applied to non-human primates by developing a model of perforant path stimulation in newborn marmoset monkeys, measuring the resulting brain damage, and blocking it with NMDA antagonists. We expect those studies to significantly advance our understanding of the mechanism of damage resulting from seizures in the immature brain.
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