Perinatal hypoxic-ischemic encephalopathy is a major cause of chronic neurologic disorders in children and adults. Developing motor systems in the brain are particularly vulnerable to perinatal injury. Unilateral carotid artery ligation and subsequent exposure to 8% oxygen in 7 day old rats leads to reproducible ischemic neuronal damage limited to forebrain ipsilateral to ligation. This is a useful small animal model for study of perinatal brain injury. Using this well characterized model, the proposal will focus on examination of the role of the excitatory neurotransmitter glutamate in the pathogenesis of ischemic neuronal injury and on identification of features of ischemic injury which are relevant in the immature brain. Hypoxia-ischemia induced alterations in the distribution and pharmacology of post-synaptic glutamate receptors will be analyzed using in vitro 3H-glutamate autoradiography. Animals treated with the neuroprotective glutamate antagonist MK -801 will be used to dissect -the relationship between receptor changes and evolution of neuronal injury. Biochemical factors that regulate high affinity glutamate uptake(HAGU) in the developing nervous system will be examined and the impact of hypoxia-ischemia on HAGU will be assessed in synaptosomes derived from lesioned brain. Chemical modulation of striatal glutamate release in immature brain and the effects of hypoxia- ischemia on glutamate release will be studied with in vivo microdialysis. This work will provide a better understanding of the neurobiology of perinatal hypoxic-ischemic brain injury and may provide a basis for development of more specific and effective therapeutic interventions.
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