Glutamate is an important excitatory neurotransmitter in both invertebrates and vertebrates. Altered glutamatergic neurotransmission is believed to be a key participant in the pathophysiology of many disorders of the nervous system, including Alzheimer's Disease, Parkinson's disease, and stroke. A large number of ionotropic glutamate receptors have been identified, many of which can combine to form functional receptors. However, it remains unclear how this diversity of glutamate receptors influences neuronal excitability and the control of behavior. The goal of the proposed research is to determine how specific glutamate receptors contribute to the control of locomotion by a simple neural circuit. We will determine how the expression and spatial organization of these receptors is regulated, we will examine the effects of mutating specific receptor subunits, we will elucidate the mechanism of action of these receptors by electrophysiological analysis, and we will use genetic strategies to discover additional genes that control the membrane expression of receptors. We have established that the locomotory control circuit in C. elegans is particularly advantageous for the study of how glutamate receptors are regulated and how they contribute to information processing by the circuit. We have also established a detailed neural map of the 10 identified C. elegans glutamate receptors. Six of these receptors, including 4 non-NMDA receptors and 2 NMDA receptors, are expressed in many of the locomotory control interneurons. We propose a variety of experimental approaches to test the hypothesis that glutamate receptors play critical roles in the control of locomotion of C. elegans. By generating mutations in these receptors, we will determine how glutamate receptors, singly and in combination, contribute to the control of locomotion. Using electrophysiological methods, we will record glutamate-evoked currents from wildtype and mutant worms. To assess receptor function, we will express cloned glutamate receptor subunits in heterologous cells and measure glutamate-gated currents. To determine whether glutamate receptors may assemble together at synapses, we will assess the subcellular co-localization of receptor subtypes. To identify genes that regulate glutamate receptor localization or membrane density of receptors, we will screen for extragenic suppressors of the dominant movement disorder observed in transgenic worms that express a dominantly active form of glutamate receptor in the locomotory control neurons.
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