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Activity-Regulated Cytoskeleton-Associated Protein Controls AMPAR Endocytosis through a Direct Interaction with Clathrin-Adaptor Protein 2

Yes / 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. / This work was supported by the BBSRC_FAPPA BB/J02127X/1 and BBSRC-BB/H018344/1 to SALC and by the FAPESP_RCUK_FAPPA 2012/50147-5 and FAPESP_Young Investigator’s grant 2009/50650-6 to LLdS. SCW was a PhD Student supported be the BBSRC/GSK PhD-CASE Studentship, LPdA is a postdoc fellow supported by FAPESP, YCJ was supported by a FAPESP scientific initiation scholarship.

Identiferoai:union.ndltd.org:BRADFORD/oai:bradscholars.brad.ac.uk:10454/8321
Date18 April 2016
CreatorsDaSilva, L.L., Wall, M.J., de Almeida, Luciana P., Wauters, S.C., Januario, Y.C., Muller, Jurgen, Corrêa, Sonia A.L.
Source SetsBradford Scholars
LanguageEnglish
Detected LanguageEnglish
TypeArticle, Accepted manuscript
Rights© 2016 DaSilva et al. Full-text reproduced in accordance with the publisher's copyright policy. This work is licensed under a Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/)., CC-BY

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