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Cover ArticleArticles, Cellular/Molecular

Synaptic Strength Is Bidirectionally Controlled by Opposing Activity-Dependent Regulation of Nedd4-1 and USP8

Samantha L. Scudder, Marisa S. Goo, Anna E. Cartier, Alice Molteni, Lindsay A. Schwarz, Rebecca Wright and Gentry N. Patrick
Journal of Neuroscience 10 December 2014, 34 (50) 16637-16649; DOI: https://doi.org/10.1523/JNEUROSCI.2452-14.2014
Samantha L. Scudder
1University of California San Diego, Section of Neurobiology, Division of Biological Sciences, La Jolla, California 92093,
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Marisa S. Goo
1University of California San Diego, Section of Neurobiology, Division of Biological Sciences, La Jolla, California 92093,
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Anna E. Cartier
2ICB International, La Jolla, California 92037,
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Alice Molteni
1University of California San Diego, Section of Neurobiology, Division of Biological Sciences, La Jolla, California 92093,
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Lindsay A. Schwarz
3Department of Biology, Howard Hughes Medical Institute, Stanford University, Stanford, California 94305, and
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Rebecca Wright
4The Salk Institute for Biological Studies, La Jolla, California 92037
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Gentry N. Patrick
1University of California San Diego, Section of Neurobiology, Division of Biological Sciences, La Jolla, California 92093,
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Abstract

The trafficking of AMPA receptors (AMPARs) to and from synapses is crucial for synaptic plasticity. Previous work has demonstrated that AMPARs undergo activity-dependent ubiquitination by the E3 ubiquitin ligase Nedd4-1, which promotes their internalization and degradation in lysosomes. Here, we define the molecular mechanisms involved in ubiquitination and deubiquitination of AMPARs. We report that Nedd4-1 is rapidly redistributed to dendritic spines in response to AMPAR activation and not in response to NMDA receptor (NMDAR) activation in cultured rat neurons. In contrast, NMDAR activation directly antagonizes Nedd4-1 function by promoting the deubiquitination of AMPARs. We show that NMDAR activation causes the rapid dephosphorylation and activation of the deubiquitinating enzyme (DUB) USP8. Surface AMPAR levels and synaptic strength are inversely regulated by Nedd4-1 and USP8. Strikingly, we show that homeostatic downscaling of synaptic strength is accompanied by an increase and decrease in Nedd4-1 and USP8 protein levels, respectively. Furthermore, we show that Nedd4-1 is required for homeostatic loss of surface AMPARs and downscaling of synaptic strength. This study provides the first mechanistic evidence for rapid and opposing activity-dependent control of a ubiquitin ligase and DUB at mammalian CNS synapses. We propose that the dynamic regulation of these opposing forces is critical in maintaining synapses and scaling them during homeostatic plasticity.

  • AMPA receptors
  • deubiquitination
  • E3 ubiquitin ligase
  • endocytosis
  • lysosome
  • ubiquitin
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The Journal of Neuroscience: 34 (50)
Journal of Neuroscience
Vol. 34, Issue 50
10 Dec 2014
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Synaptic Strength Is Bidirectionally Controlled by Opposing Activity-Dependent Regulation of Nedd4-1 and USP8
Samantha L. Scudder, Marisa S. Goo, Anna E. Cartier, Alice Molteni, Lindsay A. Schwarz, Rebecca Wright, Gentry N. Patrick
Journal of Neuroscience 10 December 2014, 34 (50) 16637-16649; DOI: 10.1523/JNEUROSCI.2452-14.2014

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Synaptic Strength Is Bidirectionally Controlled by Opposing Activity-Dependent Regulation of Nedd4-1 and USP8
Samantha L. Scudder, Marisa S. Goo, Anna E. Cartier, Alice Molteni, Lindsay A. Schwarz, Rebecca Wright, Gentry N. Patrick
Journal of Neuroscience 10 December 2014, 34 (50) 16637-16649; DOI: 10.1523/JNEUROSCI.2452-14.2014
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Keywords

  • AMPA receptors
  • deubiquitination
  • E3 ubiquitin ligase
  • endocytosis
  • lysosome
  • ubiquitin

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