Arc mRNA and protein are targeted to synapses that have experienced particular patterns of activity.
Arc is induced in response to the sorts of brief behavioral experience that can lead to long-lasting synaptic modifications.
Finally, Arc mRNA is induced in neuron types that are thought to participate in enduring synaptic modification in response to behavioral experience (neurons in the hippocampus and cerebral cortex).
There are a number of pieces of the puzzle that are still missing, however. First, it remains to be established whether Arc protein in fact plays a role in activity-induced synaptic modification. Additional clues about the role of the protein will likely come from studies of the protein itself and its interactions with other functional molecules of the postsynaptic density. Certainly, the fact that Arc may be linked to the NMDA receptor in some way is an important clue in this regard. But even if Arc does not play a direct role, the way that Arc is handled by neurons reveals the existence of previously unknown RNA trafficking mechanisms that could be used for sorting other mRNAs that do play a key role in bringing about activity-dependent modifications.
The fascinating properties of Arc should not make us lose sight of the fact that other mRNAs are present in dendrites constitutively, including the mRNAs for molecules that have been strongly implicated in activity-dependent synaptic modification (the mRNA for the a-subunit of CAMII kinase, for example). These mRNAs that are present constitutively provide an opportunity for local regulation of the synthesis of key signaling molecules via translational regulation. Hence, gene expression at individual synapses is likely to be regulated in a complex fashion. One level of regulation would be in the mRNAs available for translation (i.e., Arc). Another level might involve regulation of translation of the mix of mRNAs that are in place, including those present constitutively (a model of which might be the translational regulation of fragile-X, refs. 26 and 27). How this is coordinated and how all of these molecules actually fit in to the molecular consolidation process remains to be established.
Thanks to Kelli Sharp and Jamie Zaffis for technical assistance. This work was supported by National Institutes of Health Grants NS12333 (O.S.) and MH 53603 (P.F.W.).
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