The experiments described in this grant application are designed to provide information about the participation of excitatory amino acids, especially glutamate, in neuronal death, development, and communication. They will utilize dispersed cultures of rat hippocampus and explant cultures to explore three aspects of the neurobiology of glutamate. These experiments should enhance our knowledge of events likely to take place during cerebral anoxin and ischemia, which are extremely important clinical problems. Major questions to be considered include: 1. What is the mechanism of glutamate neurotoxicity and how does it relate to anoxic neuronal injury? a. Is elevated intracellular calcium directly related to cell death? b. Is decreased intracellular pH directly related to cell death? c. Are perturbations of second messengers/modulators/intracellular enzymes causally linked to neuronal death? d. Are there circumstances when glutamate alters neurons without killing them? e. What is the sequence of morphological changes which neurons undergo prior to glutamate-induced death? 2. Does ongoing release of glutamate alter the structure or function of developing neurons? a. Will chronic blockage of glutamate receptors modify the dendritic structure of hippocampal neurons? b. Is the level of intracellular calcium in cultured neurons partially regulated by ongoing glutamate release and synaptic activity? 3. What factors control the release of synaptic glutamate in vitro? a. What is the peak concentration of glutamate released-into the synaptic cleft? b. Is calcium always required for glutamate release?
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