TY - JOUR T1 - Arc controls AMPAR endocytosis through a direct interaction with clathrin-adaptor protein 2 JF - eneuro JO - eneuro DO - 10.1523/ENEURO.0144-15.2016 SP - ENEURO.0144-15.2016 AU - Luis L. DaSilva AU - Mark J. Wall AU - Luciana P. de Almeida AU - Sandrine C. Wauters AU - Yunan C. Januário AU - Jürgen Müller AU - Sonia A. L. Corrêa Y1 - 2016/05/05 UR - http://www.eneuro.org/content/early/2016/05/04/ENEURO.0144-15.2016.abstract N2 - 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.Significance Statement: The direct binding of Arc to the clathrin-adaptor protein 2 complex discovered in this study provides the crucial mechanistic link between the activity-dependent expression of Arc and the targeting of specific synaptic AMPA receptors for endocytosis. The interaction between Arc and AP-2 is crucial for many forms of synaptic plasticity and may provide a novel target for therapeutic intervention. ER -