The nervous system relays and processes information by releasing neurotransmitters at the points of specialized synaptic contact between neurons. In the mammalian nervous system, glutamate serves as the major excitatory neurotransmitter and is implicated in processes as diverse as learning and memory, epilepsy, and cell death associated with stroke and degenerative neurological disorders. The understanding of synaptic signaling by glutamate has been limited by the lack of knowledge of the molecular machinery required for the development and function of the glutamanergic synapse.
The aim of this proposal is to pursue a combined genetic and electrophysiological study of glutamate receptor function in the simple nervous system of the soil nematode Caenorhabditis elegans. Putative glutamate receptors have been identified in C. elegans and a deletion mutation in one receptor, glr-1, interferes only with the worms' withdrawal response to mechanical stimulation. This response is primarily mediated by a single bifunctional neuron, ASH, that mediated withdrawal to both mechanical and osmotic stimuli. To learn more about glutamate receptor function in C. elegans, it is proposed to clone additional genes encoding glutamate receptors and to define the expression of these gene products in the C. elegans nervous system. To examine the behavioral role of glutamine receptors, genetic techniques will be used to generate transgenic worms that lack one or several glutamate receptor subunits. In vertebrates, excessive glutamate or exposure to excitotoxic drugs that activate glutamate receptors can cause a receptor-dependent neuronal death. In C. elegans, these same excitotoxins can cause paralysis or death of the worm. Additional genes required for glutamanergic function will be identified by screening for genes that when mutated confer a recessive resistance to drug-induced paralysis. The electrophysiological and pharmacological properties of C. elegans glutamate receptors will be studied by functional expression in Xenopus oocytes. To characterize glutamate receptor function in vivo, whole-cell currents will be recorded from identified neurons in C. elegans. The proposed studies will help us learn how glutamate receptors contribute to neuronal function in C. elegans. These studies will also identify additional genes required for glutamanergic signaling and may contribute to our understanding of stroke, excitotoxicity, and neuronal death.
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