Arc regulates spine morphology and maintains network stability in vivo

Gladstone Institute of Neurological Disease and the Keck Program in Striatal Physiology, San Francisco, CA 94158, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 10/2010; 107(42):18173-8. DOI: 10.1073/pnas.1006546107
Source: PubMed


Long-term memory relies on modulation of synaptic connections in response to experience. This plasticity involves trafficking of AMPA receptors (AMPAR) and alteration of spine morphology. Arc, a gene induced by synaptic activity, mediates the endocytosis of AMPA receptors and is required for both long-term and homeostatic plasticity. We found that Arc increases spine density and regulates spine morphology by increasing the proportion of thin spines. Furthermore, Arc specifically reduces surface GluR1 internalization at thin spines, and Arc mutants that fail to facilitate AMPAR endocytosis do not increase the proportion of thin spines, suggesting that Arc-mediated AMPAR endocytosis facilitates alterations in spine morphology. Thus, by linking spine morphology with AMPAR endocytosis, Arc balances synaptic downscaling with increased structural plasticity. Supporting this, loss of Arc in vivo leads to a significant decrease in the proportion of thin spines and an epileptic-like network hyperexcitability.

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Available from: Carol Wilkinson, Aug 10, 2015
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    • "Its expression is confined almost exclusively to excitatory neurons of the hippocampus and neocortex, with little or no expression in glia (Vazdarjanova et al., 2006). Arc is also involved in regulating dendritic spines via actin remodeling, as mice lacking Arc have reduced dendritic spine density (Peebles et al., 2010). Arc mRNA, which is induced by calcium influx through voltage-gated calcium channels and N-methyl-D-aspartate receptors (NMDARs), is trafficked to dendrites and synthesized at synaptic sites (Korb and Finkbeiner, 2011). "
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    ABSTRACT: Activity-regulated cytoskeleton-associated protein (Arc) is an immediate early gene that is expressed almost exclusively in glutamatergic neurons. Arc protein is enriched in the postsynaptic density (PSD) and colocalizes with the N-methyl-D-aspartate receptor (NMDAR) complex. Arc transcription is positively modulated by NMDAR activity and is important for dendritic spine plasticity. Genetic ablation of serine racemase (SR-/-), the enzyme that converts L-serine to D-serine, a coagonist at the NMDAR, reduces dendritic spine density in the hippocampus. Here we demonstrate that SR deficient (SR-/-) mice also have reduced Arc protein expression in the hippocampus that can be reversed with chronic D-serine administration in adulthood. Furthermore, D-serine treatment partially rescues the hippocampal spine deficit in SR-/- mice. These results demonstrate the importance of D-serine in regulating the hippocampal expression of Arc in vivo. In addition, our findings underscore the potential utility of using the glycine modulatory site agonist D-serine to treat disorders that exhibit Arc and dendritic spine dysregulation as a consequence of NMDAR hypofunction, such as schizophrenia.
    Neurochemistry International 06/2014; 75. DOI:10.1016/j.neuint.2014.05.015 · 3.09 Impact Factor
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    • "MEF2-VP16 activation induced a robust decrease in dendritic spine density in WT mice (À44%), but not in Arc KO littermates (+3%; Figure 3B). Similar to previous results in the hippocampus in vivo, we observed that spine density in GFP-only transfected neurons was not different between WT and Arc KO littermates (Plath et al., 2006; but see Peebles et al., 2010). These results indicate that Arc is necessary for the structural synapse elimination in response to MEF2 activation. "
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    ABSTRACT: Experience refines synaptic connectivity through neural activity-dependent regulation of transcription factors. Although activity-dependent regulation of transcription factors has been well described, it is unknown whether synaptic activity and local, dendritic regulation of the induced transcripts are necessary for mammalian synaptic plasticity in response to transcription factor activation. Neuronal depolarization activates the myocyte enhancer factor 2 (MEF2) family of transcription factors that suppresses excitatory synapse number. We report that activation of metabotropic glutamate receptor 5 (mGluR5) on the dendrites, but not cell soma, of hippocampal CA1 neurons is required for MEF2-induced functional and structural synapse elimination. We present evidence that mGluR5 is necessary for synapse elimination to stimulate dendritic translation of the MEF2 target gene Arc/Arg3.1. Activity-regulated cytoskeletal-associated protein (Arc) is required for MEF2-induced synapse elimination, where it plays an acute, cell-autonomous, and postsynaptic role. This work reveals a role for dendritic activity in local translation of specific transcripts in synapse refinement.
    Cell Reports 05/2014; 7(5). DOI:10.1016/j.celrep.2014.04.035 · 8.36 Impact Factor
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    • "Therefore, restoration of Nrcam expression by TMT may ensure an adequate level of plasticity after injury. Arc, also known as Arg3.1, is not only involved in plasticity of synaptic strength (long-term potentiation or depression) but also in structural plasticity of dendritic spines [55]–[58]. Therefore, a decrease in the basal Arc level may lead to dysregulated spine remodeling occurring caudal to the injury level [59]. Furthermore, Arc has been implicated in regulating the homeostatic plasticity that maintains the neuronal threshold of excitability in response to chronic changes in synaptic activity [36]. "
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    ABSTRACT: Traumatic spinal cord injury (SCI) often leads to debilitating loss of locomotor function. Neuroplasticity of spinal circuitry underlies some functional recovery and therefore represents a therapeutic target to improve locomotor function following SCI. However, the cellular and molecular mechanisms mediating neuroplasticity below the lesion level are not fully understood. The present study performed a gene expression profiling in the rat lumbar spinal cord at 1 and 3 weeks after contusive SCI at T9. Another group of rats received treadmill locomotor training (TMT) until 3 weeks, and gene expression profiles were compared between animals with and without TMT. Microarray analysis showed that many inflammation-related genes were robustly upregulated in the lumbar spinal cord at both 1 and 3 weeks after thoracic injury. Notably, several components involved in an early complement activation pathway were concurrently upregulated. In line with the microarray finding, the number of microglia substantially increased not only in the white matter but also in the gray matter. C3 and complement receptor 3 were intensely expressed in the ventral horn after injury. Furthermore, synaptic puncta near ventral motor neurons were frequently colocalized with microglia after injury, implicating complement activation and microglial cells in synaptic remodeling in the lumbar locomotor circuitry after SCI. Interestingly, TMT did not influence the injury-induced upregulation of inflammation-related genes. Instead, TMT restored pre-injury expression patterns of several genes that were downregulated by injury. Notably, TMT increased the expression of genes involved in neuroplasticity (Arc, Nrcam) and angiogenesis (Adam8, Tie1), suggesting that TMT may improve locomotor function in part by promoting neurovascular remodeling in the lumbar motor circuitry.
    PLoS ONE 02/2014; 9(2):e88215. DOI:10.1371/journal.pone.0088215 · 3.23 Impact Factor
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