ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2014
Synaptic strength is bidirectionally controlled by opposing activity-dependent regulation of Nedd4-1 and USP8.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 55 papers.
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Who cites it
55 citing papers in PubMed, 82 citations in OpenAlex.
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- Activation of silent synapses driven by emerging technologies: mechanisms, disease associations, and prospects for clinical translation.Frontiers in synaptic neuroscience · 2026Review
- Convergence and divergence of molecular mechanisms in Hebbian and homeostatic plasticity.Frontiers in synaptic neuroscience · 2026Review
- Benchmarking In-Cell Proteomics for Profiling Neuroblastoma Cell Differentiation and the Ubiquitin-Proteasome System.Journal of proteome research · 2025Article
- AMPA Receptors in Synaptic Plasticity, Memory Function, and Brain Diseases.Cellular and molecular neurobiology · 2025Review
- SENP6 restricts the IFN-I-induced signaling pathway and antiviral activity by deSUMOylating USP8.Cellular & molecular immunology · 2024Article
- Molecular Mechanisms of AMPA Receptor Trafficking in the Nervous System.International journal of molecular sciences · 2023Review
- Loss of Depalmitoylation Disrupts Homeostatic Plasticity of AMPARs in a Mouse Model of Infantile Neuronal Ceroid Lipofuscinosis.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2023Article
- Schizophrenia-associated NRXN1 deletions induce developmental-timing- and cell-type-specific vulnerabilities in human brain organoids.Nature communications · 2023Article
- Impaired OTUD7A-dependent Ankyrin regulation mediates neuronal dysfunction in mouse and human models of the 15q13.3 microdeletion syndrome.Molecular psychiatry · 2023Article
- The DUB Club: Deubiquitinating Enzymes and Neurodevelopmental Disorders.Biological psychiatry · 2022Review
- Review
- Attenuation of HECT-E3 ligase expression rescued memory deficits in 3xTg-AD mice.Frontiers in aging neuroscience · 2022Article
- Memory destabilization during reconsolidation: a consequence of homeostatic plasticity?Learning & memory (Cold Spring Harbor, N.Y.) · 2021Article
- Historical perspective and progress on protein ubiquitination at glutamatergic synapses.Neuropharmacology · 2021Review
- The WD40-Repeat Protein WDR-20 and the Deubiquitinating Enzyme USP-46 Promote Cell Surface Levels of Glutamate Receptors.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2021Article
- Deubiquitylating enzymes in neuronal health and disease.Cell death & disease · 2021Review
- Remodeling without destruction: non-proteolytic ubiquitin chains in neural function and brain disorders.Molecular psychiatry · 2021Review
- Disease-associated synaptic scaffold protein CNK2 modulates PSD size and influences localisation of the regulatory kinase TNIK.Scientific reports · 2020Article
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Authors and funding
7 authors at 4 institutions in 1 country.
Funding
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.