The immediate early gene, Arc (activity-regulated cytosekeletal-associated protein), regulates multiple forms of protein synthesis-dependent synaptic plasticity, including long-term potentiation (LTP), long-term-depression (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. During LTP consolidation in the dentate gyrus of adult rats, sustained translation of dendritically transported RNA is required for stable expansion of F-actin at activated synapses. Understanding the translational regulation of Arc and other dendritically localized mRNAs may therefore give fundamental insights into the fine-control of consolidation at the synaptic level. Here, we sought to identify microRNA regulators of Arc. MicroRNAs are an important class of regulators which pair in a sequence-specific manner to the 3' UTR of target mRNAs, resulting in translation repression through recruitment of the RNA-induced silencing complex. At active synapses, derepression of microRNAs could function in protein synthesis-dependent plasticity. Target prediction algorithms (CrossLink and TargetScan) predicted possible miRNA binding sites in the Arc 3'UTR. Initial validation was performed by co-transfecting HEK cells with microRNA precursors and luciferase constucts expressing the wildtype Arc 3'UTR or Arc 3'UTR with mutations within the predicted seed-region for microRNA binding. Primary hippocampal neuronal cultures were used to validate the effects on Arc protein expression following overexpression and antimir-induced inhibition of select microRNAs. Supported by the Research Council of Norway.

Reference: 

Bramham CR, Alme MN, Bittins M, Kuipers SD, Nair RR, Pai B, Panja D, Schubert M, Soule J, Tiron A, Wibrand K. (2010) Exp Brain Res 200,125–140.