New views of Arc, a master regulator of synaptic plasticity

Department of Brain and Cognitive Sciences, The Picower Institute for Learning and Memory, and Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
Nature Neuroscience (Impact Factor: 16.1). 01/2011; 14(3):279-84. DOI: 10.1038/nn.2708
Source: PubMed


Many proteins have been implicated in synaptic and experience-dependent plasticity. However, few demonstrate the exquisite regulation of expression and breadth of functional importance as the immediate early gene product Arc. Here we review and attempt to synthesize the disparate views of Arc in neuronal function. The main conclusion garnered from this body of work is that Arc is a critical effector molecule downstream of many molecular signaling pathways and that dysregulation of Arc expression can have dire consequences for normal brain function.

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Available from: Jason Shepherd, Aug 22, 2014
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    • "By applying retroviral vector-mediated cell labeling, we compared mature granule cells born 5 days after SE to those naturally born with respect to dendritic morphology, intrinsic membrane properties, synaptic connectivity, and magnitude of cellular activity in the resting condition and after being activated by transient seizure activity. The magnitude of cellular activity was indicated by the expression of activity-regulated cytoskeletalassociated protein (Arc), which has been widely used as a marker of neuronal activation (Guzowski et al., 2005; Shepherd and Bear, 2011). "
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    ABSTRACT: To understand the potential role of enhanced hippocampal neurogenesis after pilocarpine-induced status epilepticus (SE) in the development of epilepsy, we quantitatively analyzed the geometry of apical dendrites, synaptic transmission, and activation levels of normotopically distributed mature newborn granule cells in the rat. SE in male Sprague-Dawley rats (between 6 and 7 weeks old) lasting for more than 2 h was induced by an intraperitoneal injection of pilocarpine. The complexity, spine density, miniature post-synaptic currents, and activity-regulated cytoskeleton-associated protein (Arc) expression of granule cells born 5 days after SE were studied between 10 and 17 weeks after CAG-GFP retroviral vector-mediated labeling. Mature granule cells born after SE had dendritic complexity similar to that of granule cells born naturally, but with denser mushroom-like spines in dendritic segments located in the outer molecular layer. Miniature inhibitory post-synaptic currents (mIPSCs) were similar between the controls and rats subjected to SE; however, smaller miniature excitatory post-synaptic current (mEPSC) amplitude with a trend toward less frequent was found in mature granule cells born after SE. After maturation, granule cells born after SE did not show denser Arc expression in the resting condition or 2 h after being activated by pentylenetetrazol-induced transient seizure activity than vicinal GFP-unlabeled granule cells. Thus our results suggest that normotopic granule cells born after pilocarpine-induced SE are no more active when mature than age-matched, naturally born granule cells.
    Frontiers in Cellular Neuroscience 10/2015; 9. DOI:10.3389/fncel.2015.00384 · 4.29 Impact Factor
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    • "The immediate early gene, ARC/ARG3.1 (activity-regulated cytoskeleton-associated protein/activity-regulated gene 3.1; here denoted as " ARC " for the gene and " Arc " for the mRNA and protein), controls diverse forms of experiencedependent synaptic plasticity and memory formation in the mammalian brain (Plath et al. 2006; Bramham et al. 2010; Korb and Finkbeiner 2011; Shepherd and Bear 2011). ARC is expressed predominantly in excitatory, glutamatergic projection neurons suggesting late evolutionary emergence and functional specialization (Campillos et al. 2006; Vazdarjanova et al. 2006; Mattaliano et al. 2007). "
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    ABSTRACT: IntroductionThe Activity-Regulated Cytoskeleton-associated (ARC) gene encodes a protein that is critical for the consolidation of synaptic plasticity and long-term memory formation. Given ARC's key role in synaptic plasticity, we hypothesized that genetic variations in ARC may contribute to interindividual variability in human cognitive abilities or to attention-deficit hyperactivity disorder (ADHD) susceptibility, where cognitive impairment often accompanies the disorder.Methods We tested whether ARC variants are associated with six measures of cognitive functioning in 670 healthy subjects in the Norwegian Cognitive NeuroGenetics (NCNG) by extracting data from its Genome-Wide Association Study (GWAS). In addition, the Swedish Betula sample of 1800 healthy subjects who underwent similar cognitive testing was also tested for association with 19 tag SNPs.ResultsNo ARC variants show association at the study-wide level, but several markers show a trend toward association with human cognitive functions. We also tested for association between ARC SNPs and ADHD in a Norwegian sample of cases and controls, but found no significant associations.Conclusion This study suggests that common genetic variants located in ARC do not account for variance in human cognitive abilities, though small effects cannot be ruled out.
    Brain and Behavior 08/2015; 5(10). DOI:10.1002/brb3.376 · 2.24 Impact Factor
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    • "[4]). Arc is strongly induced by convulsive seizures, and its expression is also increased in response to neuronal activity that occurs during salient experiences , such as sensory stimulation, novelty and spatial exploration, suggesting that Arc plays a role in the synaptic changes that encode these experiences (reviewed in [5] [6] [7] [8] [9]). In support of this idea, Arc knockout mice have deficits in LTP and LTD and in long term memory formation. "
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    ABSTRACT: The Activity-regulated cytoskeleton-associated protein, Arc, is an immediate-early gene product implicated in various forms of synaptic plasticity. Arc promotes endocytosis of AMPA type glutamate receptors and regulates cytoskeletal assembly in neuronal dendrites. Its role in endocytosis may be mediated by its reported interaction with dynamin 2 (Dyn2), a 100 kDa GTPase that polymerizes around the necks of budding vesicles and catalyzes membrane scission. Enzymatic and turbidity assays are used in this study to monitor effects of Arc on dynamin activity and polymerization. Arc oligomerization is measured using a combination of approaches, including size exclusion chromatography, sedimentation analysis, dynamic light scattering, fluorescence correlation spectroscopy, and electron microscopy. We present evidence that bacterially-expressed His6-Arc facilitates the polymerization of Dyn2 and stimulates its GTPase activity under physiologic conditions (37°C and 100 mM NaCl). At lower ionic strength Arc also stabilizes pre-formed Dyn2 polymers against GTP-dependent disassembly, thereby prolonging assembly-dependent GTP hydrolysis catalyzed by Dyn2. Arc also increases the GTPase activity of Dyn3, an isoform of implicated in dendrite remodeling, but does not affect the activity of Dyn1, a neuron-specific isoform involved in synaptic vesicle recycling. We further show in this study that Arc (either His6-tagged or untagged) has a tendency to form large soluble oligomers, which may function as a scaffold for dynamin assembly and activation. The ability of Arc to enhance dynamin polymerization and GTPase activation may provide a mechanism to explain Arc-mediated endocytosis of AMPA receptors and the accompanying effects on synaptic plasticity. This study represents the first detailed characterization of the physical properties of Arc. Copyright © 2015. Published by Elsevier B.V.
    Biochimica et Biophysica Acta 03/2015; 1850(6). DOI:10.1016/j.bbagen.2015.03.002 · 4.66 Impact Factor
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