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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    • "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; 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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    • "Recently, it has been found that UBE3A is a regulator of activityregulated cytoskeleton-associated protein (ARC) [96], a protein instrumental in removing AMPA receptors from the postsynaptic density [97], a process required for experience-dependent "
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    ABSTRACT: The activity-dependent structural and functional plasticity of dendritic spines has led to the long-standing belief that these neuronal compartments are the subcellular sites of learning and memory. Of relevance to human health, central neurons in several neuropsychiatric illnesses, including autism related disorders, have atypical numbers and morphologies of dendritic spines. These so-called dendritic spine dysgeneses found in individuals with autism related disorders are consistently replicated in experimental mouse models. Dendritic spine dysgenesis reflects the underlying synaptopathology that drives clinically relevant behavioral deficits in experimental mouse models, providing a platform for testing new therapeutic approaches. By examining molecular signaling pathways, synaptic deficits, and spine dysgenesis in experimental mouse models of autism related disorders we find strong evidence for mTOR to be a critical point of convergence and promising therapeutic target. Copyright © 2015. Published by Elsevier Ireland Ltd.
    Neuroscience Letters 01/2015; 601. DOI:10.1016/j.neulet.2015.01.011 · 2.03 Impact Factor
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