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% 02 in 7 day old rats leads to reproducible ischemic neuronal damage limited to forebrain ipsilateral to the 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 synaptic mechanisms in the pathogenesis of ischemic neuronal injury, in particular the role of the excitatory neurotransmitter glutamate, 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. The impact of hypoxia-ischemia on pre-synaptic high affinity glutamate uptake will be examined in synaptosomes derived from striatum, a major target for injury. The pattern of hypoxia-ischemia induced glutamate release will be studied using regional in vivo microdialysis in lesioned rat pups. This work will provide a better understanding of the neurobiology of perinatal ischemic brain injury and may provide a basis for development of more specific and effective therapeutic interventions.
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