Tumor Necrosis Factor-α Signaling Maintains the Ability of Cortical Synapses to Express Synaptic Scaling
Open accessAbstract
Glial tumor necrosis factor-α (TNFα) is essential for scaling up of synapses during prolonged activity blockade, but whether TNFα is an instructive or permissive signal is not known. Here we show in rat cortical neurons that the effects of TNFα and activity blockade are not additive; whereas TNFα increased AMPA quantal amplitude at control synapses, TNFα reduced quantal amplitude at prescaled synapses, demonstrating state-dependent effects of TNFα signaling on the scaling process. Whereas synaptic scaling during prolonged activity blockade [24 h tetrodotoxin (TTX)] was prevented by blocking TNFα signaling, early scaling (6 h TTX) was not, unless TNFα signaling was first blocked for 24 h. Moreover, when synapses were prescaled, prolonged (24 h) but not brief (6 h) blockade of TNFα signaling reversed scaling. Finally, prolonged block of TNFα signaling modified the synaptic localization of several scaffold proteins, suggesting that maintenance of postsynaptic density composition is TNFα dependent. Together, these data suggest that TNFα is not an instructive signal for scaling but rather is critical for maintaining synapses in a plastic state in which synaptic scaling can be expressed.
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Blocking TNFa signaling for 24 h before blocking activity with TTX prevented both early and late scaling.
“Further, blocking TNFa signaling for 24 h before blocking activity with TTX, prevented both early and late scaling (Steinmetz and Turrigiano 2010).”
From Homeostatic Synaptic Plasticity: Local and Global Mechanisms for Stabilizing Neuronal Function (2012) · cites this paper as Steinmetz and Turrigiano 2010
The Results show that 24 hours of TNFα blockade before 6 hours of TTX prevented early scaling. They also show that TNFα blockade prevented scaling during 24 hours of TTX, but that was simultaneous treatment—not 24 hours of blockade before TTX. The cited paper therefore supports both outcomes, but not the claimed pretreatment sequence for late scaling. (LLM, conf=0.85)
Experimental — accuracy not yet measuredSynaptic scaling in vitro requires TNFa and Arc signaling.
“Interestingly, the delayed potentiation in visual cortex following lid suture requires TNFa and Arc signaling (Kaneko et al. 2008;McCurry et al. 2011) as does synaptic scaling in vitro (Shepherd et al. 2006;Stellwagen and Malenka 2006;Steinmetz and Turrigiano 2010); however, both these manipulations likely affect many forms of plasticity, so it still remains to be seen if synaptic scaling”
From Homeostatic Synaptic Plasticity: Local and Global Mechanisms for Stabilizing Neuronal Function (2012) · cites this paper as Steinmetz and Turrigiano 2010
The Discussion (page unavailable) says glial-derived TNFα is critical for maintaining synapses in a state where synaptic scaling can be expressed. It does not establish that scaling requires Arc signaling; searches for Arc and its full protein name found no supporting passage in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredScaling and TNFa are neither additive nor simply occlusive.
“Unlike TTX treatment, acute TNFa application does not scale up mini amplitude and adding TNFa to prescaled synapses actually reduces synaptic strength, indicating that scaling and TNFa are neither additive nor simply occlusive (Steinmetz and Turrigiano 2010).”
From Homeostatic Synaptic Plasticity: Local and Global Mechanisms for Stabilizing Neuronal Function (2012) · cites this paper as Steinmetz and Turrigiano 2010
Adding TNFa to prescaled synapses reduces synaptic strength.
“Unlike TTX treatment, acute TNFa application does not scale up mini amplitude and adding TNFa to prescaled synapses actually reduces synaptic strength, indicating that scaling and TNFa are neither additive nor simply occlusive (Steinmetz and Turrigiano 2010).”
From Homeostatic Synaptic Plasticity: Local and Global Mechanisms for Stabilizing Neuronal Function (2012) · cites this paper as Steinmetz and Turrigiano 2010
TNFa signaling is not necessary for induction of early (6 h) scaling, but becomes essential for maintenance of scaling during prolonged (>24 h) activity blockade.
“TNFa signaling was not necessary for the induction of early (6 h) scaling, but became essential for maintenance of scaling during prolonged (.24 h) activity blockade.”
From Homeostatic Synaptic Plasticity: Local and Global Mechanisms for Stabilizing Neuronal Function (2012) · cites this paper as Steinmetz and Turrigiano 2010
Acute TNFa application does not scale up mini amplitude.
“Unlike TTX treatment, acute TNFa application does not scale up mini amplitude and adding TNFa to prescaled synapses actually reduces synaptic strength, indicating that scaling and TNFa are neither additive nor simply occlusive (Steinmetz and Turrigiano 2010).”
From Homeostatic Synaptic Plasticity: Local and Global Mechanisms for Stabilizing Neuronal Function (2012) · cites this paper as Steinmetz and Turrigiano 2010
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Cites
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Self-citation
- Authors
- Steinmetz, C. C., & Turrigiano, G. G.
- Affiliations
- Brandeis University (US)
- Corresponding author
- Turrigiano, Gina G.
- ORCID
- Turrigiano, Gina G.
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2010-11-03
- Volume
- 30
- Issue
- 44
- Pages
- 14685-14690
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3063078
- OpenAlex
- W2080930754
- Cited by
- 146
- References
- 5
- Citations by year
- 2026: 2 · 2025: 6 · 2024: 8 · 2023: 4 · 2022: 9 · 2021: 11 · 2020: 13 · 2019: 7 · 2018: 6 · 2017: 9 · 2016: 9 · 2015: 10 · 2014: 12 · 2013: 18 · 2012: 14
- FWCI
- 5.18
- 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 Institutes of Health
- National Institute of Neurological Disorders and Stroke (R01 NS-36853, R01NS036853)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural dynamics and brain function
- Keywords
- TNF-α, synaptic scaling, activity-dependent synaptic plasticity, cortical synapses, tetrodotoxin, postsynaptic density, scaffold proteins, glial signaling
- MeSH terms
- Animals, Animals, Newborn, Cells, Cultured, Cerebral Cortex, Cytoskeletal Proteins, Neural Pathways, Synaptic Transmission, Neuronal Plasticity, Synapses, Tetrodotoxin, Time Factors, Tumor Necrosis Factor-alpha, Signal Transduction, Receptors, AMPA, Rats, Long-Evans, Sodium Channel Blockers, Rats, Post-Synaptic Density
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