Synaptic scaling mediated by glial TNF-α
Abstract
Two general forms of synaptic plasticity that operate on different timescales are thought to contribute to the activity-dependent refinement of neural circuitry during development: (1) long-term potentiation (LTP) and long-term depression (LTD), which involve rapid adjustments in the strengths of individual synapses in response to specific patterns of correlated synaptic activity, and (2) homeostatic synaptic scaling, which entails uniform adjustments in the strength of all synapses on a cell in response to prolonged changes in the cell's electrical activity. Without homeostatic synaptic scaling, neural networks can become unstable and perform suboptimally. Although much is known about the mechanisms underlying LTP and LTD, little is known about the mechanisms responsible for synaptic scaling except that such scaling is due, at least in part, to alterations in receptor content at synapses. Here we show that synaptic scaling in response to prolonged blockade of activity is mediated by the pro-inflammatory cytokine tumour-necrosis factor-alpha (TNF-alpha). Using mixtures of wild-type and TNF-alpha-deficient neurons and glia, we also show that glia are the source of the TNF-alpha that is required for this form of synaptic scaling. We suggest that by modulating TNF-alpha levels, glia actively participate in the homeostatic activity-dependent regulation of synaptic connectivity.
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Acute application of TNFa or conditioned media from activity-blocked cultures increases mEPSC amplitude.
“This model is based on the observations that TNFa levels are elevated by prolonged (48 h) activity blockade, acute application of TNFa (or conditioned media from activity-blocked cultures) increases mEPSC amplitude, and scaling up in response to prolonged activity blockade is prevented by blocking TNFa signaling (Beattie et al. 2002;Stellwagen et al. 2005;Stellwagen and Malenka 2006).”
From Homeostatic Synaptic Plasticity: Local and Global Mechanisms for Stabilizing Neuronal Function (2012) · cites this paper as Stellwagen and Malenka 2006
Scaling up in response to prolonged activity blockade is prevented by blocking TNFa signaling.
“This model is based on the observations that TNFa levels are elevated by prolonged (48 h) activity blockade, acute application of TNFa (or conditioned media from activity-blocked cultures) increases mEPSC amplitude, and scaling up in response to prolonged activity blockade is prevented by blocking TNFa signaling (Beattie et al. 2002;Stellwagen et al. 2005;Stellwagen and Malenka 2006).”
From Homeostatic Synaptic Plasticity: Local and Global Mechanisms for Stabilizing Neuronal Function (2012) · cites this paper as Stellwagen and Malenka 2006
Prolonged activity blockade with TTX increases glial release of TNFa, which acts on neurons to enhance AMPAR insertion and scale up mEPSC amplitude.
“It was recently proposed that prolonged activity blockade (with TTX) increases glial release of TNFa, which then acts on neurons to enhance AMPAR insertion and scale up mEPSC amplitude (Stellwagen and Malenka 2006).”
From Homeostatic Synaptic Plasticity: Local and Global Mechanisms for Stabilizing Neuronal Function (2012) · cites this paper as Stellwagen and Malenka 2006
TNFa levels are elevated by prolonged (48 h) activity blockade.
“This model is based on the observations that TNFa levels are elevated by prolonged (48 h) activity blockade, acute application of TNFa (or conditioned media from activity-blocked cultures) increases mEPSC amplitude, and scaling up in response to prolonged activity blockade is prevented by blocking TNFa signaling (Beattie et al. 2002;Stellwagen et al. 2005;Stellwagen and Malenka 2006).”
From Homeostatic Synaptic Plasticity: Local and Global Mechanisms for Stabilizing Neuronal Function (2012) · cites this paper as Stellwagen and Malenka 2006
The TNFa involved in scaling up synaptic strengths in response to TTX originates from glia rather than neurons.
“Interestingly, the TNFa involved in scaling up synaptic strengths in response to TTX originates from glia rather than neurons, because wild-type neurons grown on TNFa 2/2 glia did not scale up synaptic strengths in response to 48 h of TTX treatment, whereas TNFa 2/2 neurons grown on wild-type glia did (Stellwagen and Malenka 2006).”
From Homeostatic Synaptic Plasticity: Local and Global Mechanisms for Stabilizing Neuronal Function (2012) · cites this paper as Stellwagen and Malenka 2006
TNFa-dependent scaling is only observed after prolonged activity block (48 h).
“Inconsistent with the above model is the observation that scaling is a gradual and cumulative process evident after as little as 4-6 h of activity blockade (Sutton et al. 2006;Ibata et al. 2008), whereas TNFa-dependent scaling was only observed after prolonged activity block (48 h) (Stellwagen and Malenka 2006).”
From Homeostatic Synaptic Plasticity: Local and Global Mechanisms for Stabilizing Neuronal Function (2012) · cites this paper as Stellwagen and Malenka 2006
Synaptic 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 Stellwagen and Malenka 2006
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- Authors
- Stellwagen, D., & Malenka, R. C.
- Affiliations
- Stanford Medicine (US)
- Corresponding author
- Malenka, Robert C.
- Venue
- Nature
- Published
- 2006-04-01
- Volume
- 440
- Issue
- 7087
- Pages
- 1054-1059
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W1542136448
- Cited by
- 1,715
- References
- 6
- Citations by year
- 2026: 73 · 2025: 66 · 2024: 72 · 2023: 70 · 2022: 102 · 2021: 102 · 2020: 117 · 2019: 80 · 2018: 87 · 2017: 94 · 2016: 80 · 2015: 92 · 2014: 92 · 2013: 104 · 2012: 103
- FWCI
- 27.28
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institutes of Health
- 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
- synaptic scaling, homeostatic plasticity, TNF-α, neuron-glia interactions, long-term potentiation, long-term depression, neural network stability
- MeSH terms
- Animals, Hippocampus, Nerve Net, Neuroglia, Neurons, Synapses, Tetrodotoxin, Tumor Necrosis Factor-alpha, Signal Transduction, Rats, Sprague-Dawley, Long-Term Potentiation, Receptors, AMPA, Receptors, Tumor Necrosis Factor, Excitatory Postsynaptic Potentials, Long-Term Synaptic Depression, Mice, Rats
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