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).”

“Exogenous TNF has been shown to induce selective cell surface expression of Ca 2 -permeable AMPARs (Beattie et al., 2002; Ogoshi et al., 2005; Stellwagen et al., 2005), and their expression has been correlated with enhanced neuronal death in models of ischemia and excitotoxicity (Hermann et al.,…”

“and phosphorylation of 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl)propanoic acid receptors, and activation of the α7 subtype of nicotinic acetylcholine receptors (Stellwagen et al., 2005; Terrando et al., 2011; Viviani et al., 2003).”

“Tumor necrosis factor (TNF)-a, another proinflammatory cytokine that shares several biological functions with IL-1h, has been shown to modulate AMPARs (Beattie et al., 2002; Stellwagen et al., 2005).”

“In the healthy brain, TNF-α is usually present at very low levels and maintains synaptic functionality mainly by increasing the surface expression of AMPARs to promote glutamatergic excitatory synaptic transmission (Stellwagen et al., 2005; Stellwagen & Malenka, 2006).”

“…albeit at much lower levels than during inflammatory reactions and are thought to be implicated in regulating homeostatic brain functions (Vitkovic et al., 2000; Bajetto et al., 2001; Beattie et al., 2002; Stellwagen et al., 2005; Stellwagen and Malenka, 2006; Kaneko et al., 2008; Boulanger, 2009).”

“The proinflammatory cytokine IL-1 significantly increases neuronal GluR2-lacking AMPARs, albeit to a lesser extent (Ogoshi et al., 2005; Stellwagen et al., 2005).”

“…increases neuronal excitability via upregulation of the -amino-3hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor (Ogoshi et al., 2005; Stellwagen et al., 2005), downregulation of glutamate transporter (Yan et al., 2014; Eidson et al., 2017), and decreased -aminobutyric acid (GABAA)…”

“As TNF, acting through TNFR1 receptors, induces the insertion of Ca permeable AMPA receptors into hippocampal pyramidal neurons [2,56] and TNF has more recently been shown to induce the insertion of GluR1 into a synaptic membrane of motor neurons, we postulated that it might induce the insertion of Ca-perm AMPAr into…”

“These include longterm potentiation (LTP) stimuli [37], cocaine administration [38], and pharmacological treatments aimed at altering activity levels in neuronal networks [39 ,40,41].”

“These studies have shown that glia released TNF-α is required for synaptic scaling through AMPAR trafficking to the membrane [92–94].”

“…subunit expression in rat forebrain long term after LPS administration (Harr et al., 2008) as well as in TNF-a receptor subtypes knockout mice (Balosso et al., 2009), and by the ability of TNF-a to induce rapid changes in AMPA receptor subunit expression and function (Stellwagen et al., 2005).”

“Bennett et al. (1998), Grell et al. (1998), Stellwagen et al. (2005), Tartaglia et al. (1993), Yang et al. (2002) and Yanga et al. (2009).”

“…affects the immune response and cytokine production, but also boosts α-amino3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA receptor) production while reducing that of GABA receptors, thus enhancing the activator synapsis and causing an extreme neural activity (Stellwagen et al., 2005).”

“Its role in the regulation of synaptic strength was first pointed out in hippocampal neurons where glial-released TNFa promoted the delivery and accumulation of Ca2+-permeable GluA1-containing AMPARs to the post-synaptic membrane (Beattie et al. 2002; Stellwagen et al. 2005).”

“hyper-excitable neurons that were susceptible to excitotoxic insults (Stellwagen et al., 2005; Stellwagen and Malenka, 2006).”

“Elsewhere, it has been shown that TNF-α induces the endocytosis of GABAA receptors in the mouse and rat hippocampus (Pribiag and Stellwagen, 2013; Stellwagen et al., 2005), concomitant with a decrease in inhibitory postsynaptic 17 currents.”

“For instance, astrocytic release of TNFα was shown to trigger the exocytosis and increased surface expression of AMPARs through a neuronal TNFR1-PI3 kinase signaling pathway (Beattie et al., 2002; Stellwagen et al., 2005).”

“The increase in AMPAR surface expression is triggered by TNFR1 and requires PI3K activity (Stellwagen et al. 2005).”

“First, we examined the effects of acute (90 min) application of TNF in the presence or absence of TTX. TNF alone significantly increased mEPSC amplitude (n 11; p 0.018), similar to previous reports (Stellwagen et al., 2005), whereas 90 min of TTX alone had no significant effect (Fig.”

“Additionally, enhanced TNF-α signaling results in the endocytosis of gamma-aminobutyric acid (GABA) A receptors and in the consequent reduction in inhibitory synaptic transmission [42].”

“For visualization of surface GluR1, GluR2, and 3-integrin levels, we used a protocol described previously (Stellwagen et al., 2005).”

“…Kawanokuchi et al., 2006; Schwartz et al., 2006; Muzio et al., 2007), which can enhance the excitatory synaptic transmission (Stellwagen et al., 2005; Lai et al., 2006; Mizuno et al., 2008), and downregulate the inhibitory Gamma Amino-Butyric acid (GABA) transmission (Stellwagen et al., 2005).”

“…that XPro1595 strongly inhibited Co 2 uptake by RGCs. Treatment with GYKI 52466, a noncompetitive AMPAR antagonist (Mellor, 2010), or Philantotoxin 343 (PhTx 343), a polyamine-derived compound that selectively antagonizes CP-AMPAR (Strømgaard et al., 2005), effectively blocked Co 2 uptake (Fig.”

“Malenka and colleagues have shown in hippocampus in vitro that after 48 hours of activity blockade, glia increase their production of a cytokine called tumour necrosis factor alpha (TNFa), which in turn leads to increased synaptic GluR1 and scaling of mEPSC amplitudes (Stellwagen et al. 2005; Stellwagen & Malenka 2006…”

“Morphine-induced TLR4 signaling increases proinflammatory cytokine production in the central nervous system (CNS) (Raghavendra et al, 2002; Shen et al, 2011a) including tumor necrosis factor (TNF).”

“Thus, we favor a second possibility, which involves the recent discovery that TNFα promotes the selective insertion of Ca-permeable AMPA receptors (AMPARs) into the neuronal cell surface (34, 35).”

“A previous electrophysiological experiment has demonstrated that CP-AMPARs can be increased by TNF at synapses by measuring mEPSCs while blocking CP-AMPARs with the antagonist HPP-spermine (in addition to synaptic activity blockade) (Stellwagen et al., 2005).”

“Indeed, TNF-α has been evidenced to facilitate the insertion of GluR2lacking AMPA receptors in the membrane [204, 220, 221].”

“TNF-α can also decrease inhibitory synaptic transmission in the spinal cord [78, 79], stimulate the release of additional pro-inflammatory cytokines, and induce proliferation of immune and glial cells to enhance neuroinflammation and pain transmission [80].”

“In hippocampal cultured neurons and slices, TNF-a promotes the insertion of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors into plasma membranes (75) and the formation of GluA2-lacking AMPA receptors (76).”

“subunit composition of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) and GABA-A receptors in vitro [13, 31, 60] and in vivo [85–88].”

“Numerous studies have indicated that homeostatic responses to increased network activity may also involve modifications to GABAergic synapses, effecting a change in the balance of network excitation and inhibition.”

“TNF-α was shown to increase the expression of AMPA glutamate receptors and reduce the expression of GABAA receptors in hippocampal neurons, thus regulating the potentiality for plastic changes in neural networks of this region of the brain [44, 45].”

“TNF-triggered synaptic effects involve perturbation of AMPA receptor trafficking (Stellwagen et al., 2005).”

“Further studies provided evidence that an exocytosis of AMPA receptor was mediated by TNFR1 and accompanied with an endocytosis of inhibitory GABAA receptors (Stellwagen et al. 2005).”

“, 2005) while decreasing the GABAmediated inhibitory synaptic strength (Stellwagen et al., 2005).”

“Some of the first evidence suggesting that microglia-derived cytokine signaling could regulate synaptic function was work demonstrating roles for TNFa in regulating the amount of surface AMPA receptors, synaptic strength, and homeostatic plasticity [24 ,25,26].”

“…propionic acid (AMPA) receptors in the aging brain, mimicking the alterations occurring in MS and EAE brains (Jasek and Griffith, 1998; Viviani et al., 2003, 2006; Stellwagen et al., 2005; Centonze et al., 2009; Viviani and Boraso, 2011; Grasselli et al., 2013).”

“TNF signaling reduces the synaptic and behavioral alteration induced by chronic haloperidol To examine the physiological correlate of the behavior, we measured the effect of subchronic haloperidol treatment on AMPAR- Overall, haloperidol leads to an increase in CP-AMPARs at MSN synapses, and these receptors contribute…”

“TNF-α modulates and influences many neuronal activities in the CNS, which include glutamatergic transmission [58–60] and gamma-aminobutyric acid (GABA) transmission [58,61,62], with an overall outcome of these alterations of an augmentation of excitatory synaptic transmission compared to inhibitory…”

“Laboratory evidence implicate TNF-a in inflammatory molecular mechanisms producing neurotoxicity, neuronal death, or neuronal dysfunction involving both TNF-glutamate (De et al., 2005; Stellwagen et al., 2005; Taylor et al., 2005) or TNF-amyloid interactions (Craft, 2006; Floden et al.”

“Differential trafficking of excitatory and inhibitory receptors has been reported [22].”

“Acute IL-6 application does not appear to regulate AMPA receptor trafficking (Stellwagen et al., 2005).”

“This signaling route could also play a role in pathological states such as post-traumatic epilepsy (Balosso et al., 2009; Volman et al., 2011) or spinal cord injury (Stellwagen et al., 2005; Ferguson et al., 2008).”

“49,50 Based on these results, it may be hypothesized that the sodium-butyrate-mediated decrease in TNF-a levels and restoration of GABAergic activity are responsible for relieving neuropathic pain in CCI models.”

“TNFa causes trafficking of excitatory receptors to the neuronal cell surface and simultaneous internalization of inhibitory receptors, resulting in a net increase in neuronal excitability [8,41,42].”

“Inflammatory cytokines (Stellwagen et al., 2005; Lai et al., 2006; Stellwagen and Malenka, 2006; Cumiskey et al., 2007; Mizuno et al., 2008; Centonze et al., 2009), resident immune cells such as microglia (Centonze et al.”

“…central immune signaling also has neuroexcitatory effects through upregulation of surface AMPA and NMDA receptors, increased conductivity of NMDA receptors, and increased spontaneous excitatory neurotransmitter release (Mandolesi et al., 2013; Stellwagen et al., 2005; Viviani et al., 2003).”

“TNF-α is known to affect dendrite morphology via the modulation of NF-κB (47) and modify synaptic strength via increased expression of AMPA receptors (31).”

“TNF effects on AMPA and GABAA receptors TNF was shown to modify both the assembly and the synaptic clustering of αamino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) by inducing the expression of extrasynaptic Ca permeable AMPAR lacking the GLUR2 subunit (Ogoshi et al., 2005; Stellwagen et al., 2005).”

“…contributors to opioid reward (Coller and Hutchinson, 2012) via their neuroexcitatory effects (Watkins et al., 2009), GABA receptor downregulation (Stellwagen et al., 2005), upregulation of AMPA/NMDA expression and function (De et al., 2003), and enhancement of neurotransmitter release (Youn et…”

“GluA2-lacking AMPARs may also be inserted through TNFR1-mediated PI3K activity (Stellwagen et al., 2005).”

“Under physiological conditions, TNF is important for regulating synaptic strength at excitatory and inhibitory synapses through mechanisms of synaptic scaling (Beattie et al., 2002; Stellwagen et al., 2005) and gliotransmission (Santello et al.”

“…TNF . p38 MAPK has been shown to play an important role in the development of inflammatory and neuropathic pain (Ji et al., 2002; Jin et al., 2003; Svensson et al., 2003, 2005, 2008; Schäfers et al., 2003a; Tsuda et al., 2004; Boyle et al., 2006; Zhuang et al., 2007; Sorkin et al., 2009;…”

“[36] demonstrated that the proinflammatory cytokine, tumor necrosis factor-a (TNF-a), up-regulates the AMPA receptor and downregulates the GABAA receptor on the cell surface of the hippocampal pyramidal neurons.”

“Prior work has shown that the glial TNFα increases trafficking of GluA2-lacking AMPA receptors to the neuronal plasma membrane, thereby increasing synaptic receptor levels (Beattie et al., 2002; Stellwagen et al., 2005; Stellwagen and Malenka, 2006; Leonoudakis et al., 2008).”

“…addition, proinflammatory cytokines also stimulate chronic release of neuroexcitatory transmitters, inhibit uptake of these neurotransmitters by the glial population, and restrict the recycling of GABA receptors (Hu et al., 2000; Bezzi et al., 2001; Stellwagen et al., 2005; Ferguson et al., 2008).”