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

DaSilva, L.L.
; 
Wall, M.J.
; 
de Almeida, Luciana P.
; 
Wauters, S.C.
; 
Januario, Y.C.
; 
Muller, Jurgen
; 
Corrêa, Sonia A.L.
Publication Date
2016-05-04
End of Embargo
Supervisor
Keywords
Arc, AMPAR, Endocytosis, Clathrin-adaptor, AP-2
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/).
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Peer-Reviewed
Yes
Open Access status
openAccess
Accepted for publication
2016-04-18
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Life Sciences Publications
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Additional title
Abstract
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.
URI
http://hdl.handle.net/10454/8321
Version
Accepted manuscript
Citation
DaSilva LL, Wall MJ, de Almeida LP, Wauters SC, Januario YC, Muller J and Correa SAL (2016) Activity-Regulated Cytoskeleton-Associated Protein Controls AMPAR Endocytosis through a Direct Interaction with Clathrin-Adaptor Protein 2. eNeuro. 3(3).
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Link to Version of Record
https://doi.org/10.1523/ENEURO.0144-15.2016
Type
Article
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