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Differential Regulation of AMPA Receptor and GABA Receptor Trafficking by Tumor Necrosis Factor-α
Open accessAbstract
The proinflammatory cytokine tumor necrosis factor-α (TNFα) causes a rapid exocytosis of AMPA receptors in hippocampal pyramidal cells and is constitutively required for the maintenance of normal surface expression of AMPA receptors. Here we demonstrate that TNFα acts on neuronal TNFR1 receptors to preferentially exocytose glutamate receptor 2-lacking AMPA receptors through a phosphatidylinositol 3 kinase-dependent process. This increases excitatory synaptic strength while changing the molecular stoichiometry of synaptic AMPA receptors. Conversely, TNFα causes an endocytosis of GABA A receptors, resulting in fewer surface GABA A receptors and a decrease in inhibitory synaptic strength. These results suggest that TNFα can regulate neuronal circuit homeostasis in a manner that may exacerbate excitotoxic damage resulting from neuronal insults.
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“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 et al. 2005
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In the citing paper
“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 et al. 2005
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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 et al. 2005
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Citations
Cites
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“These new synaptic AMPARs are likely replaced over time by GluR2-containing receptors, because HPP-spermine had no effect on mEPSCs recorded from control neurons despite the finding that constitutive TNF release is necessary to maintain normal levels of surface AMPARs.”
BackgroundInfluentialAMPA Receptor Trafficking and Synaptic Plasticity
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BackgroundSelf-citationHomeostatic plasticity in the developing nervous system
Turrigiano, G. G., & Nelson, S. B. (2004) · Nature Reviews Neuroscience · doi:10.1038/nrn1327 · Cited by 2,485 · cited 9×
“…circuit activity is pharmacologically reduced, excitatory synapses are strengthened and inhibitory synapses weakened (Turrigiano and Nelson, 2004), at least in part through changes in the synaptic surface expression of AMPARs and GABAA receptors (Kilman et al., 2002; Turrigiano and Nelson, 2004).”
BackgroundResultInfluentialSignal transduction by tumor necrosis factor and its relatives.
Baud, V., & Karin, M. (2001) · Trends in Cell Biology · doi:10.1016/s0962-8924(01)02064-5 · Cited by 1,741 · cited 3×
“TNFR1 initiates signaling through an array of downstream pathways, most known for their roles in gene expression and apoptosis (Pan et al., 1997; Baud and Karin, 2001).”
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“Recently, the proinflammatory cytokine tumor necrosis factor- (TNF ) was found to be a novel, gliareleased factor that increases the surface expression of AMPARs (Beattie et al., 2002).”
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“In contrast, consistent with our previous results (Beattie et al., 2002), a recombinant soluble form of the TNF receptor TNFR1 (sTNFR), which binds endogenous TNF (Bezzi et al., 2001), decreased surface GluR1 staining (10 g/ ml; 72 5%; n 59) (Fig.”
BackgroundResultReinsertion or Degradation of AMPA Receptors Determined by Activity-Dependent Endocytic Sorting
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“It is possible that the antibodies to GluR1 might somehow sterically inhibit antibody staining of surface GluR2, and, therefore, we used an alternative technique, biotinylation of surface AMPARs (Ehlers, 2000; Kim and von Zastrow, 2003), to reexamine whether GluR2 surface expression was increased by TNF .”
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“Similarly, the effects of TNF could contribute to the modification of circuit behavior that underlies the hyperalgesia after peripheral nerve damage, a neuropathological state that involves glia-released cytokines, including TNF (Watkins et al., 2001; Milligan et al., 2003).”
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“However, glycine treatment caused an increase in surface expression of both GluR1 and GluR2 (Lu et al., 2001; Man et al., 2003), although we observed a large increase in surface GluR1 with TNF but no significant change in surface GluR2.”
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BackgroundGodlevsky, L., Drozdova, G., Kobolev, E., Mustyatsa, V., & Polyasnyi, V. A. (2013) · Bulletin of experimental biology and medicine · doi:10.1007/s10517-013-1942-6 · Cited by 5
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BackgroundThe NF-κB Family in Learning and Memory
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BackgroundPittà, M. D. (2020) · Springer eBooks · doi:10.1007/978-1-4614-7320-6_100691-1 · Cited by 21
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BackgroundOliveira, L., Pinheiro, D. J. L. L., Rodrigues, L., Reyes-Garcia, S. Z., Nishi, E., Ormanji, M., Faber, J., & Cavalheiro, E. (2019) · Scientific Reports · doi:10.1038/s41598-019-40969-w · Cited by 4
Iacopetta, K., Collins‐Praino, L. E., Buisman‐Pijlman, F. T. A., & Hutchinson, M. R. (2018) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2018.07.008 · Cited by 4
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Does the MK2-dependent Production of TNFα Regulate mGluR-dependent Synaptic Plasticity?
Hogg, E. L., Müller, J., & Corrêa, S. A. L. (2015) · Current Neuropharmacology · doi:10.2174/1570159x13666150624165939 · Cited by 3
“Exposure of neurons to TNFα disrupts synaptic scaling by increasing excitatory AMPAR expression and decreasing inhibitory γ-aminobutyric acid (GABAA) receptor expression [19].”
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BackgroundMontenegro, Y. H. A., Bobermin, L. D., Sesterheim, P., Salvato, R. S., Anschau, F., de Oliveira, M. J. S., Wyse, Â. T. D. S., Netto, C. A., Gonçalves, C.-A. S., Quincozes‐Santos, A., et al. (2023) · Journal of NeuroVirology · doi:10.1007/s13365-023-01156-w · Cited by 4
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“2 The circulating proinflammatory mediators dysregulate the cellular underpinning of learning and memory, such as changes to the expression and composition of AMPA receptors, 3 promotion of neuronal hyperexcitability, 4 and impairing long-term potentiation induction and maintenance.”
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Neuroimmune Modulation of Synaptic Function
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BackgroundInfluentialManohar, S., Russo, F. Y., Seigel, G., & Salvi, R. (2020) · Neuroscience · doi:10.1016/j.neuroscience.2020.04.010 · Cited by 2
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BackgroundChoi, J., Choi, S., Kim, S., Kim, H., Lim, B., Hwang, H., Jong, H.-C., Kim, K. J., Oh, S., & Shin, J.-S. (2019) · Annals of Child Neurology · doi:10.26815/acn.2019.00038 · Cited by 2
“Altogether TNF-α leads to increase seizure susceptibility [22,23].”
BackgroundEl-Ansary, A. K., Hassan, S. A., Anwar, M., Shmais, G. A. A., Bhat, R. S., Hashish, A. F., Khalil, R. G., AL-Ayadhi, L. Y., & Meguid, N. A. (2015) · Journal of Pediatric Neurology · doi:10.3233/jpn-140660 · Cited by 3
“Tumor necrosis factor-alpha and interleukin-6 as two remarkably high pro-inflammatory cytokines in Saudi autistics [26] which alter excitatory and inhibitory synaptic responses [27].”
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“2005) or tumor necrosis factor-alpha receptor activation (Stellwagen et al., 2005).”
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“…NFkappa B (Theiss et al., 2009), may induce insulin resistance (Moller, 2001), bipolar disorder (Tilleux and Herman, Oriaifo et al. 183 2007) and epilepsy (Vezzani et al., 2011) via increases in excitatory synaptic strength and decreases in inhibitory synaptic strength (Stellwagen et al., 2005).”
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“Early interest in a synaptic role for TNF α came from evidence that exogenous application of TNF α rapidly increases plasma membrane recruitment of GluA2-lacking AMPARs (Beattie et al., 2002; Stellwagen et al., 2005).”
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“GWI Impairs Post-Synaptic Protein Expression (Without Affecting Pre-Synaptic or Astrocytic Synaptic Protein Levels), which is Attenuated after Neutralizing solTNF Neuroinflammation, specifically the inflammatory cytokine TNF, is a known regulator of synaptic plasticity (60).”
BackgroundPRRT2 Mutation and Serum Cytokines in Paroxysmal Kinesigenic Dyskinesia
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Expression, Function and Targeting of the ATP-gated P2X7 receptor in epilepsy
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“In addition, as a secondary effect of TNF-α induction from IL-1β activation, AMPA-receptor density and activity increases in neurons, which results in an increase in Ca+2 influx (Stellwagen et al., 2005).”
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Immunity meets inhibition: Immunomodulation of cortical inhibitory synaptic networks
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Metadata
- Authors
- Stellwagen, D., Beattie, E. C., Seo, J. Y., & Malenka, R. C.
- Affiliations
- Stanford Medicine (US)
- California Pacific Medical Center (US)
- Corresponding author
- Malenka, Robert C.
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2005-03-23
- Volume
- 25
- Issue
- 12
- Pages
- 3219-3228
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6725093
- OpenAlex
- W2134209166
- Cited by
- 985
- References
- 74
- Citations by year
- 2026: 44 · 2025: 35 · 2024: 59 · 2023: 54 · 2022: 60 · 2021: 64 · 2020: 61 · 2019: 48 · 2018: 49 · 2017: 41 · 2016: 43 · 2015: 57 · 2014: 45 · 2013: 53 · 2012: 61
- FWCI
- 11.57
- 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 (MH63394)
- National Institute of Mental Health (F32MH065752, R37MH063394, R01MH063394, MH065752, MH63394)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Keywords
- TNF-α, AMPA receptor trafficking, receptor internalization, TNFR1, phosphatidylinositol 3-kinase, excitotoxicity, hippocampal pyramidal neurons, inflammatory cytokines, synaptic homeostasis
- MeSH terms
- Animals, Animals, Newborn, Antibodies, Cells, Cultured, Dose-Response Relationship, Radiation, Drug Interactions, Electric Stimulation, Enzyme Inhibitors, Hippocampus, Immunohistochemistry, Neural Inhibition, Synaptic Transmission, Neurons, Tumor Necrosis Factor-alpha, Blotting, Western, Gene Expression, Receptors, GABA, Receptors, AMPA, Patch-Clamp Techniques, Excitatory Postsynaptic Potentials, Biotinylation, Protein Transport, Receptors, Tumor Necrosis Factor, Type I, Rats, In Vitro Techniques
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