Targeting of mRNA to postsynaptic sites on neuronal dendrites
A fundamental aspect of gene expression in neurons involves delivery of certain mRNAs to synaptic sites on dendrites, where they are locally translated at synapses. Local translation of mRNA plays a critical role in synaptic consolidation, the process through which early transient changes in synaptic effi cacy become more enduring. Mechanisms of transport and localization have been revealed through studies of a unique immediate early gene (IEG) called Arc (activity-regulated cytoskeleton-associated protein), AKA Arg 3.1. Arc is strongly induced by intense neuronal activity, but is unique amongst known IEGs because its mRNA is rapidly delivered into dendrites. A remarkable feature of Arc is that newly-synthesized Arc mRNA localizes selectively at active synapses. Live cell imaging studies using a GFP-based labeling system reveal that exogenously expressed Arc constructs assemble into particles that are transported at rates up to 65 μm/minute, which would allow the delivery of an mRNA from the nucleus to synapses on distal dendrites within minutes. Transcripts that contain the 3’UTR of Arc localize in a highly selective manner at the base of dendritic spines, indicating that the signals mediating both dendritic transport and synaptic targeting are present in the 3’UTR of Arc mRNA. Docking of Arc mRNA at active synapses depends on NMDA receptor activation, a rapid polymerization of actin in spines, and local activation of MAP kinase. Continued strong activation of synapses after Arc mRNA is docked at synapses triggers Arc mRNA degradation; the mechanisms underlying this activity-dependent mRNA degradation remain to be identifi ed. I will discuss how this mechanism might play a role in stabilizing changes in synapses induced by activity.