Activity-dependent growth of new dendritic spines is regulated by the proteasome
Open accessAbstract
Growth of new dendritic spines contributes to experience-dependent circuit plasticity in the cerebral cortex. Yet the signaling mechanisms leading to new spine outgrowth remain poorly defined. Increasing evidence supports that the proteasome is an important mediator of activity-dependent neuronal signaling. We therefore tested the role of the proteasome in activity-dependent spinogenesis. Using pharmacological manipulations, glutamate uncaging, and two-photon imaging of GFP-transfected hippocampal pyramidal neurons, we demonstrate that acute inhibition of the proteasome blocks activity-induced spine outgrowth. Remarkably, mutation of serine 120 to alanine of the Rpt6 proteasomal subunit in individual neurons was sufficient to block activity-induced spine outgrowth. Signaling through NMDA receptors and CaMKII, but not PKA, is required to facilitate spine outgrowth. Moreover, abrogating CaMKII binding to the NMDA receptor abolished activity-induced spinogenesis. Our data support a model in which neural activity facilitates spine outgrowth via an NMDA receptor- and CaMKII-dependent increase in local proteasomal degradation.
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The UPS has previously been shown to be implicated in spine stability.
“Interestingly, the UPS has previously been shown to be implicated in spine stability”
From Proteasome phosphorylation regulates cocaine-induced sensitization (2018) · cites this paper as Hamilton et al., 2012
In Results, under “Proteasome Inhibition Acutely Reduces New Spine Outgrowth” (page unavailable), the paper reports reduced spine loss after proteasome inhibition, which provides some support for a link to spine stability. It attributes that reduction to fewer new, mostly transient spines rather than demonstrating an effect on the stability of existing spines. (LLM, conf=0.83)
Experimental — accuracy not yet measuredThe findings are in stark contrast to previous data showing significant differences in synapse strength, synaptic scaling, and activity-dependent spine outgrowth.
“These findings are in stark contrast to previous data which showed significant differences in synapse strength, synaptic scaling, and activity-dependent spine outgrowth (Djakovic et al., 2009, 2012; Hamilton et al., 2012)”
From Altered Phosphorylation of the Proteasome Subunit Rpt6 Has Minimal Impact on Synaptic Plasticity and Learning (2021) · cites this paper as Hamilton et al., 2012
Acute proteasomal inhibition or ectopic expression of an Rpt6 S120A phospho-dead mutant blocks activity-dependent new spine generation.
“We also demonstrated that the acute proteasomal inhibition or ectopic expression of an Rpt6 S120A phospho-dead mutant blocks activity-dependent new spine generation (Hamilton et al., 2012).”
From Altered Phosphorylation of the Proteasome Subunit Rpt6 Has Minimal Impact on Synaptic Plasticity and Learning (2021) · cites this paper as Hamilton et al., 2012
Acute inhibition of the proteasome or expression of Rpt6 S120A blocks activity-dependent new spine generation.
“Furthermore, we demonstrated that the acute inhibition of the proteasome or expression of Rpt6 S120A phospho-dead mutant blocks activity-dependent new spine generation (Hamilton et al., 2012).”
From Altered Phosphorylation of the Proteasome Subunit Rpt6 Has Minimal Impact on Synaptic Plasticity and Learning (2021) · cites this paper as Hamilton et al., 2012
Rpt6 is involved in the regulation of synaptic strength and activity-dependent generation of new spines.
“We have previously shown that Rpt6 is involved in the regulation of synaptic strength and activity-dependent generation of new spines (Djakovic et al., 2012; Hamilton et al., 2012).”
From Proteasome phosphorylation regulates cocaine-induced sensitization (2018) · cites this paper as Hamilton et al., 2012
Experimental — accuracy not yet measured
Rpt6 phosphorylation and proteasome function regulate the formation of new dendritic spines.
“recently Rpt6 phosphorylation and proteasome function have been shown to regulate the formation of new dendritic spines (Hamilton et al., 2012).”
From Proteasome phosphorylation regulates cocaine-induced sensitization (2018) · cites this paper as Hamilton et al., 2012
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- Authors
- Hamilton, A. M., Oh, W. C., Vega-Ramirez, H., Stein, I. S., Hell, J. W., Patrick, G. N., & Zito, K.
- Affiliations
- University of California, Davis (US)
- University of California San Diego (US)
- Corresponding author
- Zito, Karen
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2012-06
- Volume
- 74
- Issue
- 6
- Pages
- 1023-1030
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC3500563
- OpenAlex
- W2113083385
- Cited by
- 164
- References
- 39
- Citations by year
- 2026: 5 · 2025: 4 · 2024: 8 · 2023: 13 · 2022: 12 · 2021: 19 · 2020: 12 · 2019: 15 · 2018: 5 · 2017: 18 · 2016: 13 · 2015: 12 · 2014: 14 · 2013: 10 · 2012: 4
- FWCI
- 5.27
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute (52005892)
- National Institute on Aging (R56AG017502, R01AG017502, AG017502)
- National Institute of General Medical Sciences (T32GM007377, GM056765, T34GM083894, GM083894, R25GM056765)
- National Institute of Neurological Disorders and Stroke (R21NS054732, R01NS062736, R01NS060847, NS054732, NS062736)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- proteasome, activity-dependent plasticity, Rpt6, NMDA receptor, CaMKII, proteasomal degradation, hippocampal pyramidal neurons, glutamate uncaging, synaptic plasticity, cerebral cortex
- MeSH terms
- Animals, Hippocampus, Leupeptins, Mutation, Neuronal Plasticity, Neurons, Synapses, Transfection, Signal Transduction, Cysteine Proteinase Inhibitors, Receptors, N-Methyl-D-Aspartate, Rats, Sprague-Dawley, Proteasome Endopeptidase Complex, Dendritic Spines, Rats, Calcium-Calmodulin-Dependent Protein Kinase Type 2
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