Differential Regulation of AMPA Receptor and GABA Receptor Trafficking by Tumor Necrosis Factor-α

“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.”

“Trafficking of these receptors is thought to underlie, at least in part, both rapid forms of synaptic plasticity and slower homeostatic changes in transmission (Malinow and Malenka, 2002; Turrigiano and Nelson, 2004).”

“…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).”

“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).”

“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).”

“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.”

“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 .”

“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).”

“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.”

“…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).”

“This condition persisted even with the long-term (24 h) TNF- treatment, suggesting that TNFR signaling might be primarily involved in the trafficking of rapid AMPAR exocytosis but not protein metabolism (19, 22, 42).”

“TNF- α may also increase AMPA receptor density in the neuronal membrane, which results in calcium entry (Stellwagen et al., 2005).”

“Cells become more permeable to Ca2+, especially via AMPA receptors, which are produced in a form lacking GluA2, the subunit that blocks Ca2+ conductance (Stellwagen et al. 2005).”

“TNFα, another SE-associated proinflammatory cytokine, enhances neuronal excitability by increasing the frequency of AMPA-dependentminiature excitatory postsynaptic currents and decreasing GABAA-mediated inhibitory synaptic strength (Stellwagen et al., 2005).”

“Studies have shown that application of TNFα in cultured hippocampal neurons induces a rapid translocation of AMPARs (within 15 min) to the postsynaptic domain in a subunit-specific manner [26, 27].”

“Also through activation of TNFR1, TNF-α was found to increase the surface AMPA receptors by exocytosis but to decrease surface GABAA receptors through a PI3 kinasedependent pathway, resulting in enhanced glutamatergic neuronal transmission and reduced inhibitory synaptic strength [98].”

“(2013) 126, 662--672 (Cipolla et al. 2012), may be the consequence of SD that results in post-SD aberrantly increased neuronal excitability (Beattie et al. 2002) and decreased inhibition (Stellwagen et al. 2005).”

“These studies have shown that TNFa triggers a change in AMPARs which can promote a shift towards surface expression of GluA2-lacking receptors (Ferguson et al., 2008; Ogoshi et al., 2005; Stellwagen, 2005).”

“Furthermore, other reports of TTX-induced homeostatic plasticity are generally supportive of this, showing increased levels of GluA2-lacking AMPARs after activity deprivation (Thiagarajan et al., 2005; Sutton et al., 2006; Aoto et al., 2008; Hou et al., 2008).”

“membranes; cytokines can also modulate glutamate receptor–mediated calcium permeability by promoting AMPAGluR2 and N-methyl-D-aspartate (NMDA)-NR2B receptor phosphorylation via PI3K or Src kinases, respectively.(16,21,30,124,125) The role of IL-1R1/TLR4 signaling pathway in seizure precipitation and recurrence involve…”

“The role of TNFR1 in the AMPAR toxicity in these studies is consistent with the findings of Stellwagen et al. (2005), who identified TNFR1 as the mediator of TNF-induced AMPAR movement to the plasma membrane.”

“The glia derived proinfl ammatory cytokine tumor necrosis factor alpha (TNF-alpha) also promotes GABAA receptor endocytosis, but at the same time AMPA receptor exocytosis, thereby infl uencing the E/I balance, which has been observed in the hippocampus (Leidenheimer, 2008; Stellwagen et al., 2005).”

“Interestingly, tumor necrosis factor alpha was recently shown to increase the density of Capermeable AMPA receptors at the neuronal plasma membrane (Stellwagen et al. 2005) and this cytokine is highly induced by IL-1b (Allan et al.”

“M1 polarization may decrease inhibitory synaptic activity to promote initiation of SD (Kunkler et al., 2005; Pribiag and Stellwagen, 2013; Stellwagen et al., 2005).”

“TNF-α is a well-known regulator of AMPAR trafficking [225, 226, 227, 228].”

“Cell-surface proteins were labeled with biotin and cell-surface GluR2 was quantified as previously described [18].”

“TNF-a also has the ability to decrease inhibitory synapses by causing endocytosis of inhibitory gamma-aminobutyric acid (GABA) receptors (Stellwagen et al., 2005).”

“The inflammatory cytokine, tissue necrosis factor-alpha (TNF-α) can lead to rapid exocytosis of Ca-AMPA channels on pyramidal neurons (Beattie et al., 2002; Ogoshi et al., 2005; Stellwagen et al., 2005), and recent studies strongly suggest that TNF-α dependent trafficking of Ca-AMPA channels contributes to neurodegene…”

“This indicates that interneurons are not involved in the effects of TNFα on excitatory synaptic activity in DG but this does not exclude the possibility that the cytokine has some effects on inhibition (Stellwagen et al., 2005).”

“…activity, resulting in a reduction in LTP and excitotoxicity resulting in neuronal and glial damage (Beattie et al., 2002; Bezzi et al., 2001; Furukawa and Mattson, 1998; Ida et al., 2008; Ren et al., 2011; Stellwagen et al., 2005; Tilleux et al., 2007; Wang et al., 2013b; Yang et al., 2005).”

“For example, Beattie et al. (2002) and Stellwagen et al. (2005) have demonstrated that glial tumor necrosis factor alpha (TNFα) facilitates membrane insertion of calcium-permeable α-amino-3-hydroxy-5-methyl4-isoxazolepropionic acid (AMPA) glutamate receptors (CPAMPARs) and internalization of…”

“Neuronal TNFR1 also has influence over Ca2+mediated cell death by increasing the membranous expression of iontropic glutamate receptor AMPA, through the activation of IP3 [71].”

“Among cytokines, TNF-a neuroregulatory function, in addition to its role in inflammatory responses, has been clearly demonstrated (Stellwagen et al., 2005).”

“For example, the cytokine TNF-a increases a-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) and decreases GABA(A) receptors on neuronal membranes, thus increasing neuronal excitability [10,12,49].”

“…it has been shown that TNF-a rapidly increases insertion of AMPA receptors to neuronal cell membranes (Beattie et al., 2002; Ogoshi et al., 2005; Stellwagen et al., 2005; Stellwagen and Malenka, 2006) through a phosphatidylinositol-3 kinase–dependent process (Stellwagen et al., 2005), leading…”

“Regardless, this technique has been used successfully to detect their very close apposition (Beattie et al., 2002; Stellwagen et al., 2005; Ferguson et al., 2006).”

“Two years later it was sequenced (Beutler et al., 1985) and found, unexpectedly, to be identical to a previously sequenced molecule, TNF (Aggarwal et al., 1985).”

“, 2002), endocytosis of GABAA receptors (Stellwagen et al., 2005) and alterations to glutamate uptake and release by glia through CXCR4 signalling (Bezzi et al.”

“In the hippocampus, TNF causes an endocytosis of GABA-A receptors, lowers surface GABA-A receptors and decreases inhibitory synaptic strength, suggesting that TNF can regulate neuronal circuit homeostasis in a manner that may exacerbate excitotoxic damage resulting from neuronal insults [125].”

“Likewise, TNF has been shown to induce a rapid insertion of AMPA receptors and endocytosis of GABAA receptors (Stellwagen et al., 2005).”

“Additionally, TNF-α leads to a change in the conformation of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor, facilitating calcium influx into the neuron, and consequent glutamate activated excitotoxicity (Stellwagen et al., 2005).”

“Prior studies have shown that TNF-a can also decrease the amount of GABAergic transmission in the hippocampus, which would also help promote seizure activity [ 37 ].”

“2008), phosphoinositide-3-kinase (PI3K) controls GluA1 insertion through the TNFα mechanism (Stellwagen et al. 2005).”

“…propionic acid) receptors at synapses, and increased TNF-a concentrations cause a rapid exocytosis of AMPA receptors in hippocampal pyramidal neurons increasing excitatory synaptic strength (Beattie et al., 2002; Ogoshi et al., 2005; Stellwagen et al., 2005; Stellwagen and Malenka, 2006).”

“TNFα causes an enhancement in the synaptic strength of glutamatergic synapses by a PI3 kinase-mediated increased surface expression of AMPA receptors (Beattie et al. 2002) and also an endocytosis of GABA-A receptors, resulting in a decrease in inhibitory synaptic strength (Stellwagen et al. 2005).”

“TNFa also regulates AMPAR and GABAA receptor trafficking [319], and astrocytic glutamate release [320].”

“Many reports have been shown that TNFa contributes to the early fast excitatory of neuron by increasing the AMPA-dependent excitatory post-synaptic current at hippocampal neurons and decreasing GABA-mediated inhibitory synaptic strength (Ogoshi et al. 2005; Stellwagen et al. 2005).”

“Similar to IL-1β, tumor necrosis factor-α can also induce neuronal excitability via up-regulation of AMPA receptors which favors the ion calcium influx into neuron and down-regulation of GABA receptors in which the inhibitory synapse strength decreases(97).”

“TNFa is reported to modulate AMPAinduced excitotoxicity (Bernardino et al., 2005), and to reduce GABA receptor (Stellwagen et al., 2005).”

“TNF-a regulates the surface expression of AMPARs, increases the growth of dendrites, and enhances synaptic connectivity (Beattie et al., 2002; Stellwagen et al., 2005; Lee et al., 2010).”

“Research has shown that TNFα is able to modulate synaptic activity by acting directly on neurons via tumor necrosis factor receptor 1 (TNFR1) (61, 62) (Figure 1).”

“The release of TNFa has been shown to enhance the exocytosis of AMPARs (Stellwagen et al. 2005).”

“Although the serum concentrations of TNF-a and the soluble TNF-a receptor increase with age [26,27], results regarding the serum TNF-a concentrations in patients with AD are inconsistent [ 28-30 ].”

“to a rapid insertion of Ca-permeable AMPA receptors in hippocampal pyramidal neurons [293].”

“Since glial-derived TNFα is more notably associated with regulating CP-AMPARs during homeostatic synaptic scaling (Beattie et al. 2002; Stellwagen et al. 2005), the observations by Lebrun-Julien and colleagues suggest that an imbalance in AMPAR synaptic scaling may lie at the heart of some chronic retinal diseases suc…”

“IL-1b increases excitatory transmission through an increase in surface expression of GluR1, but IL-6 and IL-10 do not produce these receptor changes (Stellwagen et al., 2005).”

“[140] In addition, TNF‐alpha increases endocytosis of GABA receptors, thus reducing inhibitory protection against excitotoxicity.[197,220] Recent studies also indicate that higher levels of TNF‐alpha, through a ceramide‐dependent mechanism, increases the phosphorylation of the NR1 NMDA receptor subunit, thus increasin…”

“Especially the pro-epileptogenic action of IL-1β and TNFα are well understood and their upregulation after ischemia could be a possible explanation for post-ischemic epileptogenesis (Stellwagen et al., 2005; Vezzani et al., 2019).”

“Notably, recent evidence posits that AMPAR subunit trafficking and synaptic transmission is regulated by TNF (Stellwagen et al., 2005), with solTNF triggering significantly increased insertions of GluA2-lacking AMPARs into the plasma membrane (Vargas and Di Polo, 2016).”

“The former effect is due to indirect impact of TNFα on potentiation of neuronal calcium influx through involvement of AMPA receptors which lack the GluR2 subunit, while the latter inhibitory effect is attributed to the stimulation of GABAA receptor endocytosis [166, 173, 174].”

“Since earlier reports have shown that astrocyte-derived tumor necrosis factor alpha (TNFa) plays a role in synaptic scaling by regulating the accumulation of AMPA receptors at the cell surface [25,62–65], it appears to be plausible that TNFa could also be involved in the denervation-induced homeostatic scaling respons…”