New views of Arc, a master regulator of synaptic plasticity

Journal name:
Nature Neuroscience
Volume:
14,
Pages:
279–284
Year published:
DOI:
doi:10.1038/nn.2708
Published online

Abstract

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.

At a glance

Figures

  1. Regulated Arc expression modulates trafficking of AMPA receptors and stabilization of LTP and LTD.
    Figure 1: Regulated Arc expression modulates trafficking of AMPA receptors and stabilization of LTP and LTD.

    (a) Arc transcription and translation are differentially regulated by glutamate receptors and voltage-sensitive calcium channels (VSCCs). Top, group 1 mGluR activation results in rapid and local translation of Arc mRNA that pre-exists in dendrites. Arc transcription in response to mGluR activation lags behind, peaking 1–2 h after activation14. Bottom, NMDA or VSCC activation results in rapid Arc transcription and a delayed increase in Arc protein through conventional translation at the cell body. (b) Arc synthesis modulates AMPAR trafficking. NMDA and/or VSCC activation induces rapid synthesis of Arc mRNA, which is subsequently translated at the cell body or in response to local mGluR activation. Translation of Arc mRNA in dendrites is inhibited by FMRP and Arc protein is rapidly degraded through Ube3a binding and subsequent ubiquitination. Arc protein increases AMPAR endocytosis, which can lead to LTD. Arc may also act to stabilize the internal pool of AMPARs so that the surface levels of AMPARs remain constant after plasticity occurs, which would lead to a sustained increase or decrease in surface AMPARs depending on the direction of the initial plasticity trigger.

  2. Arc regulates neural circuit homeostasis.
    Figure 2: Arc regulates neural circuit homeostasis.

    (a,b) Neuronal activity regulates Arc protein expression, which can act as a sensor for the amount of activity a neuron experiences in an epoch of time. Chronic changes in neuronal activity result in homeostatic processes that maintain a relative constant neuronal output. Many mechanisms have been implicated in these homeostatic changes; two important mechanisms are synaptic scaling of AMPARs (a) and modification of the LTP and LTD threshold (b). Arc has been shown to be critical for synaptic scaling of AMPARs but may also be involved in setting the threshold for LTP versus LTD. These processes are not mutually exclusive and may act in concert, depending on the precise activity patterns the neuron is subjected to. θm denotes modification threshold.

  3. Arc is required for bidirectional experience-dependent plasticity in visual cortex in vivo.
    Figure 3: Arc is required for bidirectional experience-dependent plasticity in visual cortex in vivo.

    (a) Experience-dependent plasticity in the visual cortex can be measured using chronic visually evoked potential (VEP) recordings in V1 layer 4. (b) Schematic of the time course of VEP changes in visual cortex after monocular deprivation. In wild-type mice, monocular deprivation results in a substantial decrease in deprived eye VEPs (black line). However, deprivation has no effect in Arc−/− mice (blue line)34. (c) Repeated exposure to gratings of a specific orientation results in SRP of VEPs in wild-type mice (black line). Mice that lack Arc do no exhibit substantial SRP (blue line)34. Thus, the visual cortex is rendered immutable by deprivation or experience in the absence of Arc.

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Affiliations

  1. 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.

    • Jason D Shepherd &
    • Mark F Bear

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The authors declare no competing financial interests.

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