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The immediate early gene, Arc (activity-regulated cytoskeletal-associated protein), regulates multiple forms of protein synthesis-dependent synaptic plasticity, including LTP, LTD, and homeostatic plasticity in the vertebrate nervous system (Bramham et al., 2010).Following LTP induction, Arc mRNA is rapidly induced and a substantial fraction of the mRNA is transported into dendrites.In the dentate gyrus in vivo, studies employing brief infusion of Arc antisense oligodeoxynucleotides (Arc AS-ODN) show that LTP consolidation requires sustained translation from new Arc mRNA for 2 to 4 hours after LTP induction.Arc synthesis during this period is necessary for phosphorylation and inhibition of the actin-severing protein, cofilin, and corresponding expansion of F-actin at synaptic sites (Messaoudi et al., 2007).F-actin content in dendritic spines is stably enhanced following LTP and necessary for stable morphological changes such as formation of mushroom spines (Fukazawa et al., 2003;Tanaka et al., 2008;Bramham et al., 2008;Hotulainen and Hoogenraad, 2010).However, the mechanisms coupling Arc to cytoskeletal dynamics and the function of F-actin expansion itself are little understood.During axonal guidance, coupling of F-actin to the translation machinery is necessary for local protein synthesis and growth cone turning (Van Horck and Holt, 2008).In the present study, we considered that Arc might regulate translation through its effects on F-actin.We find that Arc synthesis is necessary for phosphorylation of the cap-binding protein, eukaryotic initiation factor 4E (eIF4E), during LTP maintenance in the dentate gyrus of anesthetized rats.This effect appears to be mediated through F-actin, as local infusion of the Factin stabilizing drug jasplakinolide after LTP induction and prior to Arc AS treatment rescued phosphorylation of eIF4E.Furthermore, Arc synthesis was required for enhanced expression of the RNA-binding protein hnRNP A2.In unstimulated dentate gyrus, Arc co-immunoprecipited with alpha-CaMKⅡ, PSD-95, and the actin-binding proteins drebrin and alpha-actinin, but not with cofilin.LTP was associated with enhanced Arc interaction with alpha-CaMKⅡ and PSD-95.