GLUTAMATE RECEPTOR TRAFFICKING IN C. ELEGANS. Recent work has shown that changes in the abundance of AMPA-type glutamate receptors at synapses are an important potential mechanism for expressing activity-dependent changes in synaptic activity. We have undertaken a comprehensive analysis of the trafficking of a C. elegans AMPA-type glutamate receptor (GLR-1). In the prior funding period, we identified a scaffolding protein (LIN-10/Mintl) required for synaptic targeting of GLR-1, we showed that anterograde trafficking of GLR-1 is regulated by voltage-activate calcium channels and CAMKII, and we showed that formation of ubiquitin-GLR-1 conjugates triggers endocytosis and post-endocytic degradation of GLR-1. In preliminary studies reported here, we identify four new genes that regulate synaptic abundance of GLR-1, one of which encodes a subunit of an SCF ubiquitin ligase. We also show that the synaptic abundance of GLR-1 is regulated by a homeostatic mechanism similar to synaptic scaling. We propose three new aims to define the biochemical mechanisms regulating GLR-1 abundance at synapses. First, we will identify the physiologically relevant targets of the SCF ubiquitin ligase and will determine how it alters the function of GLR-1 synapses. Second, we will determine what aspect of GLR-1 trafficking is regulated by genes discovered in our screen for GLR-1 mislocalization mutants and whether these defects are an indirect consequence of a failure to localize other proteins. Third, we will determine whether synaptic scaling is bi-directional, and whether it is triggered by glutamate, postsynaptic depolarization, or by neuropeptides. And we will determine what aspects of GLR-1 trafficking are regulated by synaptic scaling. In summary, changes in the synaptic abundance of AMPA receptors has been proposed as a mechanism for producing activity-dependent changes in synaptic strength, and hence in learning and memory. Given the strong conservation of these pathways across phylogeny, it is likely that our experiments will provide new insights into the mechanisms underlying these fundamental aspects of synaptic cell biology.
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