Synaptic strength is bidirectionally controlled by opposing activity-dependent regulation of Nedd4-1 and USP8
Open accessAbstract
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.
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Bicuculline treatment stimulates GluA2 ubiquitination on K882, and AMPAR ubiquitination has been shown to be required for homeostatic scaling-down.
“Bicuculline treatment stimulates GluA2 ubiquitination on K882 (Widagdo et al., 2015), very close to the Y876 and S880 phosphorylation sites, and AMPAR ubiquitination has been shown to be required for homeostatic scaling-down (Scudder et al., 2014).”
From The AMPA Receptor Code of Synaptic Plasticity (2018) · cites this paper as Scudder et al., 2014
In the section on homeostatic downscaling (pages not supplied), the paper reports increased AMPAR ubiquitination after bicuculline treatment and shows that Nedd4-1 knockdown prevents downscaling of surface AMPARs and synaptic strength. It establishes that Nedd4-1 is required, but does not directly show that ubiquitination of AMPARs themselves is required. The GluA2 K882 claim is attributed to a different citation and is not part of this verdict. (LLM, conf=0.84)
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Ca2+-Triggered (de)ubiquitination Events in Synapses
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- Authors
- Scudder, S. L., Goo, M. S., Cartier, A. E., Molteni, A., Schwarz, L. A., Wright, R., & Patrick, G. N.
- Affiliations
- University of California San Diego (US)
- Howard Hughes Medical Institute (US)
- Salk Institute for Biological Studies (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2014-12-10
- Volume
- 34
- Issue
- 50
- Pages
- 16637-16649
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC4261092
- OpenAlex
- W1990587513
- Cited by
- 81
- References
- 41
- Citations by year
- 2026: 5 · 2025: 6 · 2024: 1 · 2023: 7 · 2022: 6 · 2021: 7 · 2020: 7 · 2019: 7 · 2018: 7 · 2017: 8 · 2016: 13 · 2015: 7
- FWCI
- 4.27
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Science Foundation
- National Institutes of Health
- U.S. Public Health Service (P50-GMO85764)
- National Institute on Aging (T-32-AG-00216, T32AG000216)
- National Institute of General Medical Sciences (P50GM085764)
- National Institute of Neurological Disorders and Stroke (R01NS060847, NS060847)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- AMPA receptor trafficking, NEDD4-1, USP8, ubiquitination, deubiquitination, synaptic plasticity, homeostatic synaptic scaling, dendritic spines, NMDA receptor, receptor internalization, lysosomal degradation, activity-dependent regulation, synaptic efficacy
- MeSH terms
- Nedd4 Ubiquitin Protein Ligases, Animals, Animals, Newborn, Cells, Cultured, Female, Humans, Male, Endopeptidases, Synapses, Protein Transport, Ubiquitin Thiolesterase, Ubiquitin-Protein Ligases, Mice, Rats, Endosomal Sorting Complexes Required for Transport, HEK293 Cells
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