Arc controls AMPAR endocytosis through a direct interaction with clathrin-adaptor protein 2

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DaSilva, Luis L. ; Wall, Mark J. ; Almeida, Luciana P. de ; Wauters, Sandrine ; Januario, Yunan C. ; Müller, Jürgen ; Corrêa, Sônia A. L. (2016)
  • Publisher: Society for Neuroscience
  • Journal: eNeuro, volume 3, issue 3 (eissn: 2373-2822)
  • Related identifiers: doi: 10.1523/ENEURO.0144-15.2016, pmc: PMC4877669
  • Subject: AMPAR endocytosis | hippocampus | 6 | : adaptor protein 2 | synaptic transmission | New Research | Adaptor protein 2, AMPAR endocytosis, clathrin-mediated endocytosis, hippocampus, neuronal excitability, synaptic transmission | neuronal excitability | clathrin-mediated endocytosis | QP
    mesheuropmc: nervous system | musculoskeletal, neural, and ocular physiology

The activity-regulated cytoskeleton-associated (Arc) protein control synaptic strength by facilitating AMPA receptor (AMPAR) endocytosis. Here we demonstrate that Arc targets AMPAR to be internalized through a direct interaction with the clathrin-adaptor protein 2 (AP-2). We show that Arc overexpression overexpression in dissociated hippocampal neurons obtained from C57BL/6 mouse reduces the density of AMPAR GluA1 subunits at the cell surface and reduces the amplitude and rectification of AMPAR-mediated miniature-excitatory postsynaptic currents (mEPSC). Mutations of Arc, that prevent the AP-2 interaction reduce Arc-mediated endocytosis of GluA1 and abolish the reduction in AMPAR-mediated mEPSC amplitude and rectification. Depletion of the AP-2 subunit µ2 blocks the Arc-mediated reduction in mEPSC amplitude, effect that is restored by re-introducing µ2. The Arc/AP-2 interaction plays an important role in homeostatic synaptic scaling as the Arc-dependent decrease in mEPSC amplitude, induced by a chronic increase in neuronal activity, is inhibited by AP-2 depletion. This data provides a mechanism to explain how activity-dependent expression of Arc decisively controls the fate of AMPAR at the cell surface and modulates synaptic strength, via the direct interaction with the endocytic clathrin adaptor AP-2.\ud
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