In a manner unique among activity-regulated immediate early genes (IEGs),
mRNA encoded by
Arc (also known as Arg3.1) undergoes rapid transport to dendrites and local synaptic translation. Despite this intrinsic appeal, relatively little is known about the neuronal and behavioral functions of
Arc or its molecular mechanisms of action. Here, we attempt to distill recent advances on
Arc spanning its transcriptional and translational regulation, the functions of the
Arc protein in multiple forms of neuronal plasticity [long-term potentiation (LTP), long-term depression (LTD), and homeostatic plasticity], and its broader role in neural networks of behaving animals. Worley and colleagues have shown that
Arc interacts with endophilin and
dynamin, creating a postsynaptic trafficking endosome that selectively modifies the expression of
AMPA-type
glutamate receptors at the excitatory synapses. Both LTD and homeostatic plasticity in the hippocampus are critically dependent on
Arc-mediated endocytosis of
AMPA receptors. LTD evoked by activation of
metabotropic glutamate receptors depends on rapid
Arc translation controlled by
elongation factor 2. Bramham and colleagues have shown that sustained translation of newly induced
Arc mRNA is necessary for
cofilin phosphorylation and stable expansion of the
F-actin cytoskeleton underlying LTP consolidation in the dentate gyrus of live rats. In addition to regulating
F-actin,
Arc synthesis maintains the activity of key translation factors during LTP consolidation. This process of
Arc-dependent consolidation is activated by the secretory
neurotrophin,
BDNF. Moore and colleagues have shown that
Arc mRNA is a natural target for nonsense-mediated mRNA decay (NMD) by virtue of its two conserved 3'-UTR introns. NMD and other related translation-dependent mRNA decay mechanisms may serve as critical brakes on
protein expression that contribute to the fine spatial-temporal control of
Arc synthesis. In studies in behaving rats, Guzowski and colleagues have shown that location-specific firing of CA3 and CA1 hippocampal neurons in the presence of theta rhythm provides the necessary stimuli for activation of
Arc transcription. The impact of
Arc transcription in memory processes may depend on the specific context of coexpressed IEGs, in addition to posttranscriptional regulation of
Arc by neuromodulatory inputs from the amygdala and other brain regions. In sum,
Arc is emerging as a versatile, finely tuned system capable of coupling changes in neuronal activity patterns to diverse forms of synaptic plasticity, thereby optimizing information storage in active networks.