Localization and local translation of Arc/Arg3.1 mRNA at synapses: some observations and paradoxes

Abstract

Arc is a unique immediate early gene whose expression is induced as synapses are being modified during learning. The uniqueness comes from the fact that newly synthesized Arc mRNA is rapidly transported throughout dendrites where it localizes near synapses that were recently activated. Here, we summarize aspects of Arc mRNA translation in dendrites in vivo, focusing especially on features of its expression that are paradoxical or that donot fit in with current models of how Arc protein operates. Findings from in vivo studies that donot quite fit include: (1) Following induction of LTP in vivo, Arc mRNA and protein localize near active synapses, but are also distributed throughout dendrites. In contrast, Arc mRNA localizes selectively near active synapses when stimulation is continued as Arc mRNA is transported into dendrites; (2) Strong induction of Arc expression as a result of a seizure does not lead to a rundown of synaptic efficacy in vivo as would be predicted by the hypothesis that high levels of Arc cause glutamate receptor endocytosis and LTD. (3) Arc protein is synthesized in the perinuclear cytoplasm rapidly after transcriptional activation, indicating that at least a pool of Arc mRNA is not translationally repressed to allow for dendritic delivery; (4) Increases in Arc mRNA in dendrites are not paralleled by increases in levels of exon junction complex (EJC) proteins. These results of studies of mRNA trafficking in neurons in vivo provide a new perspective on the possible roles of Arc in activity-dependent synaptic modifications.

Dendritic trafficking faces physiologically critical speed-precision tradeoffs

“…(Kim and Martin, 2015) identified three mRNAs that were uniformly distributed in cultured Aplysia sensory neurons, but were targeted to synapses at the level of protein expression by localized translation (supporting option b). In contrast, the expression of Arc mRNA is closely matched to the pattern of Arc protein in granule cells of the dentate gyrus (possibly supporting option a; Steward et al, 1998; Farris et al, 2014; Steward et al, 2014). Trafficking kinetics do not just differ according to cargo identity – the same type of molecular cargo can exhibit diverse movement statistics in single-particle tracking experiments (Dynes and Steward, 2007).…”

Plasticity of Spine Structure: Local Signaling, Translation and Cytoskeletal Reorganization

“…(Mayford et al, 1996; Tiruchinapalli et al, 2003; Sutton et al, 2006; Butko et al, 2012; Steward et al, 2015; Yoon et al, 2016). In particular, dendritic localization of CaMKIIα mRNA has been suggested to be important for LTP and learning (Miller et al, 2002).…”

RNA‐binding proteins of the NXF (nuclear export factor) family and their connection with the cytoskeleton

“…Connection of the translation machinery to the cytoskeleton is supported by elongation factor 1 (EF1), an actin‐binding protein (Liu et al, ; Van Horck & Holt, ). Reorganization of the actin cytoskeletal network and MAP‐kinase activation are required for Arc (activity‐regulated cytoskeleton‐associated) mRNA targeting to recently activated synapses and are essential for memory storage and learning (Steward, Farris, Pirbhoy, Darnell, & Driesche, ).…”