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.
Highlights
It is widely believed that memory storage involves modifications of synaptic properties that are induced by specific patterns of activity, and that enduring forms of plasticity require gene expression and mRNA translation (Kandel, 2001; Dudai, 2002; Martin and Morris, 2002)
SELECTIVE LOCALIZATION OF Arc mRNA AT ACTIVE SYNAPSES Arc is expressed as an immediate early gene (IEG) so transcription is strongly induced by synaptic activity
Arc is expressed at low levels overall; for example, fluorescence in situ hybridization (FISH) reveals low levels of expression in the hippocampus except for a few neurons scattered in the granule cell layer of the dentate gyrus (DG) (Figures 1A,D)
Summary
It is widely believed that memory storage involves modifications of synaptic properties that are induced by specific patterns of activity, and that enduring forms of plasticity require gene expression and mRNA translation (Kandel, 2001; Dudai, 2002; Martin and Morris, 2002). A useful term to refer to the process through which initially transient and labile changes are rendered more permanent is “synaptic consolidation.” This term recognizes the formal similarity to the process of memory consolidation, through which labile memories become more resistant to disruption over time. Identifying the genes that are critical for synaptic modifications and defining how the gene products act has been a long-standing goal of modern neuroscience. In this regard, mechanisms that could allow activitydependent alterations of individual synapses or small clusters of synapses in a way that involves gene transcription and mRNA translation are of particular interest (Steward and Schuman, 2003; Hirokawa, 2006; Schuman et al, 2006)
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