Glutamate is an important excitatory neurotransmitter in both invertebrates and vertebrates. Altered glutamatergic neurotransmission is believed to be a key factor in the pathophysiology of many disorders of the nervous system, including Alzheimers disease, Parkinson's disease, and stroke. A large number of ionotropic glutamate receptor subunits have been identified, many of which can combine to form functional receptors. However, it remains unclear how specific glutamate receptors are distributed to defined synapses and how their function contributes to neuronal information processing and the control of behavior. In C. elegans, we have demonstrated that AMPA (GLR-1, GLR-2), kainate (GLR-3, GLR-6) and NMDA (NMR-1) receptors contribute to specific avoidance and foraging behaviors. Using a genetic approach we have identified a CUB-domain transmembrane protein, SOL-1, that co-localizes with GLR-1 and is absolutely required for AMPA receptor function. We have also demonstrated that glutamate-gated currents can be recorded from Xenopus oocytes that express C. elegans AMPA receptors, but only if they are co-expressed with SOL-1 and STG-1, a distant homologue of vertebrate stargazin that we recently discovered. We now propose to extend these results and provide a mechanistic understanding of how different classes of iGluRs are distributed to and maintained at specific synapses, how they participate in synaptic communication, and how they contribute to the behavior of C. elegans. Using electrophysiological methods, we will record glutamate-evoked currents from wild-type and mutant worms. To assess receptor function, we will express cloned glutamate receptor subunits in heterologous cells and measure glutamate-gated currents. To determine which glutamate receptor subtypes localize together at synapses, we will assess the subcellular distribution of receptor subtypes. To identify genes that regulate glutamate receptor localization, function, or their membrane density, we will screen for additional suppressors of a hyper-reversal phenotype in transgenic C. elegans that express a gain-of-function lurcher variant of the GLR-1 AMPA receptor.
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