The experiments of this proposal continue our studies of gene expression at synapses--a project that began with our discovery of synapse-associated polyribosome complexes (SPRCs). The central hypotheses that have guided our work are: 1) That SPRCs synthesize certain key protein constituents of the postsynaptic site, including some of the important functional molecules of the synapse; 2) that this local synthesis is critical for constructing and modifying synapses; 3) that the synthetic activity of synapse-associated polyribosomes is regulated in part by synaptic activity.The current experiments continue our studies of the selective targeting of the transcript of a unique immediate early gene (lEG) to dendrites. This gene, termed activity-regulated cytoskeleton-associated protein (Arc) is strongly induced by physiological activity like other lEGs, but is unique because its mRNA is rapidly delivered throughout dendrites. Our studies of the trafficking of Arc mRNA have demonstrated that: 1) newly-synthesized Arc mRNA is rapidly delivered into dendrites based on a targeting signal in the mRNA sequence; 2) Arc mRNA localizes selectively at recently-active synapses; 3) both the transcription of Arc mRNA in the nucleus, and the targeting of the newly synthesized transcript to active synapses are triggered by NMDA receptor activation. Importantly, Arc protein is a component of the synaptic junction, and appears to be one of the proteins that are part of a multi-protein signaling complex. The experiments of the present proposal will further characterize the mechanisms underlying the dendritic transport of Arc mRNA and the selective delivery of Arc to active synapses. We will: 1) define the signal transduction mechanisms that mark synapses for mRNA targeting; 2) identify the cell biological mechanisms underlying mRNA transport and localization; 3) define the """"""""zip codes"""""""" within Arc mRNA that route the mRNA into dendrites and the localization signals that mediate docking at the synapse. These studies will allow us to further define how local translation of mRNAs at synapses regulates synapse function, especially as synapses are being modified in an activity-dependent fashion.
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