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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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“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).”
BackgroundControl of Synaptic Strength by Glial TNFα
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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).”
BackgroundMethodResultInfluentialSelf-citationBezzi, P., Domercq, M., Brambilla, L., Galli, R., Schols, D., De Clercq, E., Vescovi, A., Bagetta, G., Kollias, G., Meldolesi, J., et al. (2001) · Nature Neuroscience · doi:10.1038/89490 · Cited by 1,102 · cited 2×
“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 .”
MethodGlial activation: a driving force for pathological pain
Watkins, L. R., Milligan, E. D., & Maier, S. F. (2001) · Trends in Neurosciences · doi:10.1016/s0166-2236(00)01854-3 · Cited by 1,091 · cited 1×
“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).”
BackgroundLu, W.-Y., Man, H., Ju, W. H., Trimble, W. S., MacDonald, J. F., & Wang, Y. T. (2001) · Neuron · doi:10.1016/s0896-6273(01)00194-5 · Cited by 935 · cited 1×
“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.”
BackgroundTumor Necrosis Factor-α: A Mediator of Focal Ischemic Brain Injury
Barone, F. C., Arvin, B., White, R. F., Miller, A., Webb, C. L., Willette, R. N., Lysko, P. G., & Feuerstein, G. Z. (1997) · Stroke · doi:10.1161/01.str.28.6.1233 · Cited by 863 · cited 2×
“…Nagatsu et al., 2000; Perry et al., 2001), and preventing its signaling in vivo can, for example, prevent or reduce neuron loss after cerebral ischemia (Dawson et al., 1996; Barone et al., 1997; Meistrell et al., 1997) and head injury (for review, see Barone et al., 1997; Shohami et al., 1999).”
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Heterogeneity and function of hippocampal macroglia
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The Contribution of Normal Pregnancy to Eclampsia
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“Active microglia secrete proinflammatory cytokines and increase local neuronal excitability by simultaneously promoting the endocytosis of GABAARs and exocytosis of excitatory α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors [21, 23].”
BackgroundStolyarova, A., Thompson, A. B., Barrientos, R. M., & Izquierdo, A. (2014) · Neuropsychopharmacology · doi:10.1038/npp.2014.309 · Cited by 23
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“Stellwagen et al. (2005), also studied the neuronal effects of applying TNF-α in hippocampal cultures and slices but used brief, 15 min, applications at 100 ng/ml (i.e., 2 nM, see the erratum to the Stellwagen et al., 2005 paper appeared in J. Neurosci.”
MethodTreatment implications of the altered cytokine-insulin axis in neurodegenerative disease
Clark, I. A., & Vissel, B. (2013) · Biochemical Pharmacology · doi:10.1016/j.bcp.2013.07.030 · Cited by 23
Tumor necrosis factor-α (TNF-α) augments AMPA-induced Purkinje neuron toxicity
Bliss, R., Finckbone, V., Trice, J., Strahlendorf, H. K., & Strahlendorf, J. C. (2011) · Brain Research · doi:10.1016/j.brainres.2011.01.059 · Cited by 19
Hypothalamus transcriptome profile suggests an anorexia-cachexia syndrome in the anx/anx mouse model
Mercader, J. M., Lozano, J. J., Sumoy, L., Dierssen, M., Visa, J., Gratacòs, M., & Estivill, X. (2008) · Physiological Genomics · doi:10.1152/physiolgenomics.90255.2008 · Cited by 26
“The increase in the expression of these genes could reflect a compensatory effect, since activation of the TNF- cascade causes an endocytosis of GABAA receptors, resulting in fewer surface receptors (72).”
BackgroundBurkovetskaya, M., Levin, S. G., & Godukhin, O. (2007) · Neuroscience Letters · doi:10.1016/j.neulet.2006.12.059 · Cited by 24
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FosL1 Is a Novel Target of Levetiracetam for Suppressing the Microglial Inflammatory Reaction
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“Past work has shown that TNF- has complex effects on synaptic plasticity and can lead to either AMPA receptor insertion or removal from the membrane depending on the circuit (Stellwagen et al., 2005; Lewitus et al., 2014).”
BackgroundThe X‐linked inhibitor of apoptosis regulates long‐term depression and learning rate
Gibon, J., Unsain, N., Gamache, K., Thomas, R. A., de León, A., Johnstone, A. D., Nader, K., Séguéla, P., & Barker, P. A. (2016) · The FASEB Journal · doi:10.1096/fj.201600384r · Cited by 19
“AMPA receptor internalization assays were performed (19).”
Pettigrew, L. C., Kryscio, R. J., & Norris, C. M. (2016) · PLoS ONE · doi:10.1371/journal.pone.0154721 · Cited by 30
“This TNFα-induced AMPA receptor exocytosis has been shown to be mediated by activation of TNF-R1 through a phospho-inositol triphosphate (PI3) kinase-dependent pathway [25].”
BackgroundYu, T., Taussig, M. D., DiPatrizio, N. V., Astarita, G., Piomelli, D., Bergman, B. C., Dell’Acqua, M. L., Eckel, R. H., & Wang, H. (2015) · PLoS ONE · doi:10.1371/journal.pone.0135113 · Cited by 21
Chronic Pain: Cytokines, Lymphocytes and Chemokines
Miguel, M., Kraychete, D. C., & Nascimento, R. M. (2015) · Inflammation & Allergy - Drug Targets · doi:10.2174/1871528114666150114170004 · Cited by 26
“Glial TNF also causes endocytosis of GABA receptors resulting in a decrease inhibitory modulation of GABAergic system [37].”
BackgroundG-Protein Coupled Receptor-Evoked Glutamate Exocytosis from Astrocytes: Role of Prostaglandins
Calì, C., Lopatář, J., Petrelli, F., Pucci, L., & Bezzi, P. (2014) · Neural Plasticity · doi:10.1155/2014/254574 · Cited by 28
“excitatory synaptic transmission by promoting the insertion of AMPA receptors at the surface [21, 22].”
Cytokine Receptors in the Brain
Conti, B., Tabarean, I. V., Sánchez-Alavez, M., Davis, C., Brownell, S. E., Behrens, M. M., & Bartfai, T. (2008) · Neuroimmune biology · doi:10.1016/s1567-7443(07)10002-8 · Cited by 22
IFNγ-Stimulated Dendritic Cell Exosomes for Treatment of Migraine Modeled Using Spreading Depression
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Lima‐Silveira, L., Accorsi‐Mendonça, D., Bonagamba, L. G. H., Almado, C. E. L., da Silva, M. P., Nedoboy, P. E., Pilowsky, P. M., & Machado, B. H. (2019) · The Journal of Physiology · doi:10.1113/jp277532 · Cited by 28
“Furthermore, experimental evidence shows that the effects of chemokines and cytokines in the CNS are not related solely to generation of immune responses; they also affect facilitation of excitatory synaptic transmission and enhancements of neuronal excitability (Viviani et al. 2003; Ogoshi et al. 2005; Stellwagen et…”
BackgroundKonefal, S., & Stellwagen, D. (2017) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.2016.0160 · Cited by 26
Self-citationMerbl, Y., Sommer, A., Chai, O., Aroch, I., Zimmerman, G., Friedman, A., Soreq, H., & Shamir, M. H. (2014) · Journal of Veterinary Internal Medicine · doi:10.1111/jvim.12462 · Cited by 22
IL-1β: an important cytokine associated with febrile seizures?
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“For example, IL-1b (Viviani et al. 2003; Yang et al. 2005), IL-6 (Samland et al. 2003; Xiaoqin et al. 2005), TNFa (Beattie et al. 2002; Stellwagen et al. 2005), IFNb (Hadjilambreva et al. 2005), CXCL10 (Ragozzino et al. 1998), CXCL1/2 (Giovannelli et al. 1998; Ragozzino et al. 1998), and the…”
InfluentialMaintenance of Synaptic Stability Requires Calcium-Independent Phospholipase A2Activity
Allyson, J., Bi, X., Baudry, M., & Massicotte, G. (2012) · Neural Plasticity · doi:10.1155/2012/569149 · Cited by 25
“There are other circumstances in which GluR1 subunits are selectively upregulated in hippocampal neurons, such as after neuronal activity inhibition elicited by prolonged blockade of AMPA receptors [103] or by tumor necrosis factor-alpha receptor activation [104].”
BackgroundFeng, M., Crowley, N. A., Patel, A., Guo, Y., Bugni, S. E., & Luscher, B. (2019) · Neuroscience · doi:10.1016/j.neuroscience.2019.03.003 · Cited by 20
“TNFα may also lead to increased Ca2+ entry into dendrites through Ca2+ permeable AMPA receptors (Stellwagen et al., 2005).”
BackgroundOne messenger shared by two systems: How cytokines directly modulate neurons
Yang, L., Huh, J. R., & Choi, G. B. (2023) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2023.102708 · Cited by 25
Homeostatic plasticity in the retina
Fitzpatrick, M. J., & Kerschensteiner, D. (2022) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2022.101131 · Cited by 31
Gobbo, D., Scheller, A., & Kirchhoff, F. (2021) · Frontiers in Neurology · doi:10.3389/fneur.2021.661408 · Cited by 25
“The precise mechanism of TNFα action in this scenario is not clear, although it is known that TNFα reduces astroglial glutamate uptake and decreases neuronal GABAA receptor expression (261, 262).”
BackgroundP2X4R contributes to central disinhibition via TNF-α/TNFR1/GABAaR pathway in post-stroke pain rats.
Lu, J.-J., Guo, X.-N., Yan, M.-Y., Yuan, X., Chen, S., Wang, Y.-Q., Zhu, J.-H., Huang, S., Shen, H.-T., Li, H., et al. (2021) · Journal of Pain · doi:10.1016/j.jpain.2021.02.013 · Cited by 20
Taskıran, A., & Avcı, O. (2020) · Neuroscience Letters · doi:10.1016/j.neulet.2020.135504 · Cited by 20
Deng, D., Wang, W., & Bao, S. (2020) · Frontiers in Neuroscience · doi:10.3389/fnins.2020.573047 · Cited by 21
Supraspinal Mechanisms of Intestinal Hypersensitivity
Любашина, О. А., Sivachenko, I. B., & Panteleev, S. S. (2020) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-020-00967-3 · Cited by 24
Wang, W., Peng, Y., Yang, H., Bu, H., Guo, G., Liu, D.-Q., Shu, B., Tian, X., Luo, A., Zhang, X., et al. (2017) · Neuropeptides · doi:10.1016/j.npep.2017.07.004 · Cited by 18
“…chemokine (Johnston et al., 2004), tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1β), resulting in the down-regulation of astrocytic glutamate transports proteins (GLT-1, GLAST) (Watkins et al., 2009) and neuronal GABA (gamma-aminobutyric acid) receptors (Stellwagen et al., 2005).”
BackgroundHuang, J., Chen, M., Du, J., Liu, H., He, Y.-J., Li, G.-L., Li, S.-Y., Liu, W.-P., & Long, X. (2016) · Neurochemical Research · doi:10.1007/s11064-016-1893-1 · Cited by 20
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Induction of TNF‐α signaling cascade in neonatal rat brain during propofol anesthesia
Popić, J., Pešić, V., Milanović, D., Lončarević-Vasiljković, N., Smiljanic, K., Kanazir, S., & Ruždijić, S. (2015) · International Journal of Developmental Neuroscience · doi:10.1016/j.ijdevneu.2015.05.003 · Cited by 20
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“Effect of Minocycline on the TNFα-induced Increase in mIPSCs from CeA Neurons The change in frequency of mIPSCs are shown after 60-ng/ml TNFα (TNFα), −60-ng/ml TNFα with one hour incubation of 60-μM minocycline (TNFα + MNC) and 60-μM moncycline incubation in the absence of TNFα (MNC).”
BackgroundResultInfluentialImmunoexcitatory mechanisms in glioma proliferation, invasion and occasional metastasis
Blaylock, R. L. (2013) · Surgical Neurology International · doi:10.4103/2152-7806.106577 · Cited by 19
“[67] One of the most consistent driving forces for pathological insertion of Ca2+permeable AMPA receptors is the presence of high levels of pro-inflammatory cytokines, in particular TNF-a[67,75,112] [Figure 2].”
BackgroundInfluentialMechanistic insight of curcumin: a potential pharmacological candidate for epilepsy
Khatoon, S., & Kalam, N. (2025) · Frontiers in Pharmacology · doi:10.3389/fphar.2024.1531288 · Cited by 17
Khan, H., Naseem, T., Kaushik, P., Narang, J., Khan, R., Panwar, S., & Parvez, S. (2024) · Ageing Research Reviews · doi:10.1016/j.arr.2024.102535 · Cited by 21
Ansarey, S. H. (2021) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2021.771144 · Cited by 21
“(111, 112), while basal levels of TNF-α are necessary for AMPA and GABAA receptor trafficking (111).”
BackgroundNeuroimmunological effects of early life experiences
Brydges, N. M., & Reddaway, J. (2020) · Brain and Neuroscience Advances · doi:10.1177/2398212820953706 · Cited by 20
“…necrosis factor alpha (TNF α ) and brain-derived neurotrophic factor (BDNF), which alter α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and N-methyl-d-aspartic acid (NMDA receptor expression in neurons (Konefal and Stellwagen, 2017; Parkhurst et al., 2013; Stellwagen et al., 2005).”
BackgroundMethoxychlor and fenvalerate induce neuronal death by reducing GluR2 expression
Umeda, K., Kotake, Y., Miyara, M., Ishida, K., Sanoh, S., & Ohta, S. (2016) · The Journal of Toxicological Sciences · doi:10.2131/jts.41.255 · Cited by 19
Volman, V., Bazhenov, M., & B, T. J. S. A. (2013) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1002856 · Cited by 18
“This relatively slow process (global effects in culture are measurable after ,48 hours of inactivity [6]) may represent a”
BackgroundTumor Necrosis Factor activation of vagal afferent terminal calcium is blocked by cannabinoids
Rogers, R., & Hermann, G. (2012) · Journal of Neuroscience · doi:10.1523/jneurosci.6220-11.2012 · Cited by 19
“TNF is also effective in amplifying glutamatergic synaptic strength by upregulating postsynaptic AMPA receptor numbers (Stellwagen et al., 2005).”
BackgroundThe Relationship Between Opioids and Immune Signalling in the Spinal Cord
Thomas, J., Mustafa, S., Johnson, J. L., Nicotra, L. L., & Hutchinson, M. R. (2015) · Handbook of experimental pharmacology · doi:10.1007/978-3-662-46450-2_11 · Cited by 22
Nagakura, I., Van Wart, A., Petravicz, J., Tropea, D., & Sur, M. (2014) · Journal of Neuroscience · doi:10.1523/jneurosci.0189-14.2014 · Cited by 18
“Interestingly, in vitro, STAT1 has a role as a binding partner of the TNFR1 receptor complex, leading to inhibition of downstream TNF signaling (Wang et al., 2000; Wesemann and Benveniste, 2003).”
BackgroundSocała, K., Jakubiec, M., Abram, M., Mlost, J., Starowicz, K., Kamiński, R. M., Ciepiela, K., Andres‐Mach, M., Zagaja, M. P., Metcalf, C. S., et al. (2024) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2024.102634 · Cited by 23
“Data show that TRPV1 is also present in some immune system cells thus it plays a pivotal role in modulating of inflammatory responses by regulation of T cell-mediated inflammation, as well as influence on levels of proinflammatory cytokines such as tumor necrosis factor (TNF-α ), interleukin-4 (IL-4), and -6 (IL-6) (B…”
BackgroundInfluentialSancho‐Alonso, M., Arenas, Y. M., Izquierdo‐Altarejos, P., Martinez‐García, M., Llansola, M., & Felipo, V. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms242417251 · Cited by 19
Pathway-specific TNF-mediated metaplasticity in hippocampal area CA1
Singh, A., Sateesh, S., Jones, O. D., & Abraham, W. C. (2022) · Scientific Reports · doi:10.1038/s41598-022-05844-1 · Cited by 21
Avalos, M. P., Guzman, A. S., Rigoni, D., Gorostiza, E. A., Sanchez, M. A., Mongi‐Bragato, B., García‐Keller, C., Perassi, E. M., Virgolini, M. B., Ramos, J. M. P., et al. (2022) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2022.01.014 · Cited by 20
Tumour Necrosis Factor in Neuroplasticity, Neurogenesis and Alcohol Use Disorder
Cooper, I. A., Beecher, K., Chehrehasa, F., Belmer, A., & Bartlett, S. E. (2020) · Brain Plasticity · doi:10.3233/bpl-190095 · Cited by 31
“TNF was found to cause GABAA receptor endocytosis in hippocampal pyramidal neurons, furthering excitatory transmission at these synapses [60].”
BackgroundKorgaonkar, A. A., Nguyen, S., Li, Y., Sekhar, D., Subramanian, D., Guevarra, J., Pang, K., & Santhakumar, V. (2019) · bioRxiv · doi:10.1101/750869 · Cited by 18
“Glia-derived TNFα has been shown to activate neuronal TNF receptor 1 (TNFR1) and mediate increases in NMDA receptor-dependent synaptic plasticity and AMPA receptor (AMPAR) surface expression (Stellwagen et al., 2005).”
BackgroundResultInflammatory cytokine receptor blockade in a rodent model of mild traumatic brain injury
Perez-Polo, J. R., Rea, H. C., Johnson, K. M., Parsley, M. A., Unabia, G. C., Xu, G.-P., Prough, D. S., DeWitt, D. S., Paulucci-Holthauzen, A. A., Werrbach‐Perez, K., et al. (2015) · Journal of Neuroscience Research · doi:10.1002/jnr.23617 · Cited by 17
“Although etanercept has been reported not to cross the intact blood–brain barrier (Sumbria et al., 2013), the SIGNIFICANCE: There are two significant findings in this report.”
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A Sublethal Dose of TNFα Potentiates Kainate-Induced Excitotoxicity in Optic Nerve Oligodendrocytes
Miller, B. A., Sun, F., Christensen, R. N., Ferguson, A. R., Bresnahan, J. C., & Beattie, M. S. (2005) · Neurochemical Research · doi:10.1007/s11064-005-6880-x · Cited by 16
“This could be accomplished by either a net increase in calcium-permeable glutamate receptors, or a change in subunit composition favoring more GluR2lacking, and therefore calcium permeable, receptors without an overall change in receptor number, as seen in hippocampal neurons (79).”
BackgroundXiao, M., Gustafsson, B., & Niu, Y. (2005) · Current Neuropharmacology · doi:10.2174/157015906775202986 · Cited by 18
“Thus, in hippocampal pyramidal cells tumor necrosis factor-alpha (TNFalpha) causes a rapid exocytosis of AMPARs but endocytosis of GABAA receptors [8, 108].”
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“TNF-α derived from glial cells significantly modulates homeostatic plasticity by stimulating the exocytosis of AMPA receptors and suppressing astrocytic glutamatergic transporters at the synaptic site (Stellwagen et al., 2005; Stellwagen and Malenka, 2006).”
Mullapudi, T., Debnath, M., Govindaraj, R., Raj, P., Banerjee, M., & Varambally, S. S. (2023) · Asian Journal of Psychiatry · doi:10.1016/j.ajp.2023.103636 · Cited by 16
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“…(1) changing the expression and activity of α-amino-3-hydroxy-5-methyl-4isoxazolepropionic acid receptor and therefore impairing plasticity (Stellwagen et al., 2005), (2) inhibiting long-term potentiation and plasticity (Murray and Lynch, 1998; Tancredi et al., 2000), (3) dysregulating…”
BackgroundNeuroinflammatory Response in Reward-Associated Psychostimulants and Opioids: A Review
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Spinal TNFα is necessary for inactivity‐induced phrenic motor facilitation
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“Among the many roles for TNFα in the healthy CNS, TNFα modulates neuronal excitability via bidirectional regulation of synaptic AMPA receptor expression (Beattie et al. 2002; Ogoshi et al. 2005; Stellwagen et al. 2005; Stellwagen & Malenka, 2006).”
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Neuroinflammation increases oxygen extraction in a mouse model of Alzheimer’s disease
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“LPS-induced cytokine release, such as TNF-α, was shown to increase excitatory synaptic strength while decreasing inhibitory synaptic strength [87].”
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“TNF-α is capable of mediating synaptic upscaling in the hippocampus through increasing the location of AMPA receptors to the neuronal membrane surface while it reduces the number of GABA A receptors (Stellwagen et al., 2005; Stellwagen & Malenka, 2006).”
BackgroundFerrucci, L., Cantando, I., Cordella, F., Angelantonio, S. D., Ragozzino, D., & Bezzi, P. (2023) · Cells · doi:10.3390/cells12242827 · Cited by 19
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“TNF-α activates the recruitment of AMPA receptors lacking the GluR2 subunit at neuronal membranes and contributes to the formation of molecular conformations that benefit Ca2+ influx into neurons and induce endocytosis of GABAA receptors [11].”
BackgroundProinflammatory cytokines and their receptors as druggable targets to alleviate pathological pain
Kalpachidou, T., Riehl, L., Schöpf, C. L., Uçar, B., & Kress, M. (2022) · Pain · doi:10.1097/j.pain.0000000000002737 · Cited by 17
Immune-Triggered Forms of Plasticity Across Brain Regions
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“Importantly, TNF1a can increase synaptic strength through modulating a-amino-3hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) trafficking.(59) Several more individual genes identified in our RNA-seq experiments also point to possible roles in aiding cognition.”
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Peripheral nerve injury potentiates excitatory synaptic transmission in locus coeruleus neurons.
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Cerebral Response to Peripheral Challenge with a Viral Mimetic
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“TNFa also promotes endocytosis of GABAA receptors, and thus, decreases the strength of inhibitory synapses [53].”
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“TNFα has been shown to regulate excitatory and inhibitory synaptic transmission through the regulation of expression of α-amino-3-hydroxy5-methyl-4-isoxazolepropionic acid receptor (AMPA) and gamma-aminobutyric acid (GABA) receptor subtype A (Stellwagen et al. 2005).”
BackgroundImpaired TNF-α Control of IP3R-mediated Ca2+ Release in Alzheimer's Disease Mouse Neurons
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“It also can induce rapid and persistent decrease of inhibitory synaptic strength by promoting GABA(A)R endocytosis, which may exacerbate excitotoxic damage resulting from neuronal insults (Pribiag and Stellwagen, 2013; Stellwagen et al., 2005).”
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“Kynurenine is further broken down in the CNS into the neuroactive metabolites kynurenic acid and quinolinic acid [15].”
BackgroundSema7A, a brain immune regulator, regulates seizure activity in PTZ‐kindled epileptic rats
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The Contribution of TNFα to Synaptic Plasticity and Nervous System Function
Stellwagen, D. (2010) · Advances in experimental medicine and biology · doi:10.1007/978-1-4419-6612-4_57 · Cited by 15
“TNFα also results in the insertion of a particular subtype of AMPA receptor, the GluR2-lacking AMPA receptor [20], which is Ca2+ permeable and therefore could also alter the threshold for synaptic plasticity or excitotoxicity.”
BackgroundMethodInfluentialSelf-citation
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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