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).”

“…literature demonstrating that proinflammatory cytokines can impact both spontaneous excitatory post synaptic currents (sEPSC) and mini excitatory postsynaptic currents (mEPSC) (28), which could be mediated through direct interaction of cytokines with receptor and ion channels in neurons (48).”

“Under physiological conditions, sTNF/TNFR1 signaling regulates glutamatergic receptor transmission and mediates glial production of pro-inflammatory cytokines (Bradley, 2008; Stellwagen, 2005; Woods et al., 2021).”

“Thus TNF is likely to drive the observed synaptic potentiation on CA1 pyramidal neurons, which may well be accompanied by decreased inhibition (Stellwagen et al., 2005), and would result in increased activity of these cells.”

“…acid (AMPA) receptors in excitatory neurons, as well as decreasing the impact of inhibitory synaptic strength through selective endocytosis of aminobutyric acid type A (GABAA) receptors (Beattie et al., 2002, Santello et al., 2011, Stellwagen et al., 2005, Stellwagen & Malenka, 2006).”

“TNF-α and IL-6 increase AMPA receptors and promote excitation, leading to glutamate excitotoxicity (Qiu et al., 1998; Stellwagen, 2005).”

“La cytokine pro-inflammatoire majeure du SNC, le TNF-α, sécrétée par les cellules gliales lorsque l’activité neuronale diminue, participe également à l’expression du synaptic scaling (Beattie et al., 2002) (Stellwagen et al., 2005) et de la plasticité synaptique hebbienne (Bains and Oliet, 2007).”

“The rapid effects on AMPA currents suggest that TLR4 signaling may promote exocytosis and surface expression of a reserve pool of GluA1, similar to the processes mediated by glia-derived TNFα in culture systems (50).”

“However, the other animal studies showed that TNF-α can protect animal from seizure through p75 activation and rearrangement of AMPA structure.(12,13) Unfortunately, Choi et al.”

“TNFα is known to trigger endocytosis of inhibitory GABAA receptors (Stellwagen et al., 2005) as well as promote increased synaptic AMPA receptor availability (Beattle et al.”

“Similar to BDNF, changes in TNFα signaling also appear to be involved in the process of synaptic scaling, although in this case it is an increase in TNFα signaling which is associated with synaptic upscaling (Stellwagen et al., 2005) and it may be more important for the maintenance rather than the induction of this sc…”

“Neuroinflammation is widely linked to learning and memory deficits, producing changes in expression and composition of AMPA receptors (Stellwagen et al, 2005), promoting neuronal hyperexcitability (Rossi et al, 2012), and impairing long-term potentiation induction and maintenance (Murray and Lynch,…”

“The latter are a major source of fast inhibitory synaptic transmission in the CNS and hence, the balance together with the opposing activity of AMPARs and levels of TNF play crucial roles in regulating the overall activity levels of the neuronal networks in the brain (Fig.”

“Similarly, TNFalpha has also been implicated in GABAA transmission decrease by endocytosis of its receptors in hippocampal pyramidal cells (Stellwagen et al. 2005).”

“Astrocyte-derived TNFα controls postsynaptic receptor levels (Stellwagen et al., 2005; Stellwagen and Malenka, 2006; Steinmetz and Turrigiano, 2010), but TNFα did not alter muting competence in our study, suggesting that the reduction in postsynaptic receptors was not responsible for the muting…”

“Moreover, TNFα can increase the expression of the AMPA receptors permeable to calcium, thereby enhancing the likelihood of excitotoxic damage (Beattie et al., 2002; Stellwagen et al., 2005).”