RT Journal Article
SR Electronic
T1 Arc controls AMPAR endocytosis through a direct interaction with clathrin-adaptor protein 2
JF eneuro
JO eneuro
FD Society for Neuroscience
SP ENEURO.0144-15.2016
DO 10.1523/ENEURO.0144-15.2016
A1 Luis L. DaSilva
A1 Mark J. Wall
A1 Luciana P. de Almeida
A1 Sandrine C. Wauters
A1 Yunan C. Januário
A1 Jürgen Müller
A1 Sonia A. L. Corrêa
YR 2016
UL http://www.eneuro.org/content/early/2016/05/04/ENEURO.0144-15.2016.abstract
AB 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.