期刊
ENEURO
卷 3, 期 3, 页码 -出版社
SOC NEUROSCIENCE
DOI: 10.1523/ENEURO.0144-15.2016
关键词
adaptor protein 2; AMPAR endocytosis; clathrin-mediated endocytosis; hippocampus; neuronal excitability; synaptic transmission
资金
- BBSRC_FAPPA [BB/J02127X/1, BBSRC-BB/H018344/1]
- FAPESP_RCUK_FAPPA [2012/50147-5]
- FAPESP_Young Investigator's Grant [2009/50650-6]
- BBSRC/GSK PhD-CASE Studentship
- FAPESP
- FAPESP scientific initiation scholarship
- BBSRC [BB/H018344/1, BB/J02127X/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/H018344/1, BB/J02127X/1] Funding Source: researchfish
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 mu 2 blocks the Arc-mediated reduction in mEPSC amplitude, an effect that is restored by reintroducing mu 2. 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.
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