Cell Reports
Volume 16, Issue 10, 6 September 2016, Pages 2711-2722
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Article
Upregulation of μ3A Drives Homeostatic Plasticity by Rerouting AMPAR into the Recycling Endosomal Pathway

https://doi.org/10.1016/j.celrep.2016.08.009Get rights and content
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Highlights

  • Cell-type-specific screen identifies transcripts involved in homeostatic synaptic scaling

  • μ3A is identified as a critical “switch point” in AMPAR trafficking

  • Upregulation of μ3A reroutes AMPAR into the recycling pathway to induce plasticity

Summary

Synaptic scaling is a form of homeostatic plasticity driven by transcription-dependent changes in AMPA-type glutamate receptor (AMPAR) trafficking. To uncover the pathways involved, we performed a cell-type-specific screen for transcripts persistently altered during scaling, which identified the μ subunit (μ3A) of the adaptor protein complex AP-3A. Synaptic scaling increased μ3A (but not other AP-3 subunits) in pyramidal neurons and redistributed dendritic μ3A and AMPAR to recycling endosomes (REs). Knockdown of μ3A prevented synaptic scaling and this redistribution, while overexpression (OE) of full-length μ3A or a truncated μ3A that cannot interact with the AP-3A complex was sufficient to drive AMPAR to REs. Finally, OE of μ3A acted synergistically with GRIP1 to recruit AMPAR to the dendritic membrane. These data suggest that excess μ3A acts independently of the AP-3A complex to reroute AMPAR to RE, generating a reservoir of receptors essential for the regulated recruitment to the synaptic membrane during scaling up.

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Present address: Novartis Pharma, Basel 4002, Switzerland

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Present address: Janelia Farm Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA

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Present address: Department of Biochemistry and Molecular Biophysics, HHMI, Columbia College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA

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Present address: Galenea Corporation, Cambridge, MA 02139, USA

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Present address: Department of Genetics, Harvard Medical School, Boston, MA 02115, USA

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