Substantial evidence suggests that glutamate (GLU) receptors mediate fast excitatory synaptic transmission in the mammalian central nervous system and are critical for generating plastic changes at synapses, which could underlie processes such as learning and memory. Synaptically released GLU has also been implicated in neuronal injury due to hypoxia-ischemia, hypoglycemia, and epilepsy. The long term objective of this project is to understand the complicated modulation of this important neurotransmitter system, and to thereby provide insight into the physiology of normal neural processes and into the pathophysiology of common neurological disorders. Primary dissociated neuronal cultures from rat hippocampus and striatum will be used in conjunction with standard whole-cell, patch-clamp recording techniques.
The specific aims of the proposed research project are: 1) to examine presynaptic and postsynaptic receptor modulation during synaptic events between monosynaptically connected pairs of neurons, 2) to elucidate cellular mechanisms of GLU receptor expression in hippocampal and striatal neurons, 3) to study modulation of excitatory transmitter release by changes in presynaptic calcium currents, and 4) to study neuronal GLU uptake mechanisms. The major strength of these experiments is the ability to study evoked monosynaptic responses between two neurons, while controlling both the extracellular and intracellular milieu. Early experiments will attempt to determine the role of desensitization in the termination of synaptic responses. Subsequent experiments will characterize cellular mechanisms of receptor expression. Quantitative physiological responses to exogenously applied agonists will serve as a measure of physiologically relevant receptor expression. The latter part of the project will explore the effects of GLU, aminophosphonobutyrate, and chemically related organic acids upon calcium currents in hippocampal and dorsal root ganglion neurons to see whether they might modulate neurotransmitter release and thereby provide a cellular explanation for certain metabolic encephalopathies which are currently poorly understood.
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