Activity-regulated cytoskeleton-associated protein controls AMPAR endocytosis through a direct interaction with clathrin-adaptor protein 2

DaSilva, Luis L.P., Wall, Mark J., de Almeida, Luciana P., Wauters, Sandrine C., Januário, Yunan C., Müller, Jürgen and Corrêa, Sônia A.L. (2016). Activity-regulated cytoskeleton-associated protein controls AMPAR endocytosis through a direct interaction with clathrin-adaptor protein 2. eNeuro, 3 (3), pp. 125-140.

Abstract

The activity-regulated cytoskeleton-associated (Arc) protein controls 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 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-EPSCs (mEPSCs). 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, an effect that is restored by reintroducing 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. These data provide 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.

Publication DOI: https://doi.org/10.1523/ENEURO.0144-15.2016
Divisions: Aston Medical School
Additional Information: Copyright © 2016 DaSilva et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed. Funded: BBSRC_FAPPA BB/J02127X/1, BBSRC-BB/H018344/1 and BBSRC/GSK PhD-CASE Studentship; and FAPESP_RCUK_FAPPA 2012/50147-5, FAPESP_Young Investigator’s Grant 2009/50650-6, FAPESP scientific initiation scholarship.
Uncontrolled Keywords: adaptor protein 2,AMPAR endocytosis,clathrin-mediated endocytosis,hippocampus,euronal excitability,synaptic transmission,Neuroscience(all)
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Related URLs: http://www.scop ... tnerID=8YFLogxK (Scopus URL)
Published Date: 2016-06-04
Authors: DaSilva, Luis L.P.
Wall, Mark J.
de Almeida, Luciana P.
Wauters, Sandrine C.
Januário, Yunan C.
Müller, Jürgen
Corrêa, Sônia A.L.

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