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).”

“TNF preferentially increases synaptic expression of GluR2-lacking AMPARs Endogenous AMPARs in hippocampal pyramidal cells are thought to be heteromultimers, with GluR1 normally forming receptors in conjunction with GluR2 (Wenthold et al., 1996).”

“Although the receptors share several of the same downstream signaling cascades, they each also have some unique signaling characteristics, including the presence of a death domain on TNFR1 (Tartaglia et al., 1991; Rath and Aggarwal, 1999; Baud and Karin, 2001).”

“Recordings of miniature EPSCs (mEPSCs) were made from 15- to 24-d-old cultures essentially as described previously (Beattie et al., 2000).”

“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).”

“Transverse hippocampal slices (400 m) were prepared from 2- to 4-week-old Sprague Dawley rats as described previously (Luscher et al., 1999).”

“This is perhaps not surprising given that the similar increases in AMPAR surface expression elicited by insulin and glycine treatments also require PI3K activity (Passafaro et al., 2001; Man et al., 2003).”

“Because recent results suggest that increases in synaptic strength as a result of homeostatic synaptic scaling (Turrigiano and Nelson, 2004) involve increased synaptic expression of GluR2-lacking AMPARs (Thiagarajan et al., 2003; Ju et al., 2004), it was of interest to examine whether TNF also increased the surface ex…”

“TNF can activate two distinct receptors, TNFR1 and TNFR2, which couple to distinct but overlapping intracellular signaling pathways (for review, see Rath and Aggarwal, 1999; Baud and Karin, 2001; MacEwan, 2002).”

“Furthermore, immune molecules such as cytokines are also thought to importantly contribute to the brain damage induced by a wide variety of neuronal insults as well as neurodegenerative diseases (New et al., 1998; Lock et al., 1999; Shohami et al., 1999; Nagatsu et al., 2000; Perry et al., 2001; Szelenyi, 2001), while…”

“Cytokines and cytokine receptor materials were from R & D Systems (Minneapolis, MN), except the TNFR2 activating antibodies, which were from Abcam (Cambridge, MA).”

“…attributable to its ability to potentiate glutamate excitotoxicity (Gelbard et al., 1993; Chao and Hu, 1994; New et al., 1998; Epstein and Gelbard, 1999; Hermann et al., 2001), which importantly contributes to much of the secondary damage after brain insults (Choi, 1994; Wrathall et al., 1994).”

“The vast majority of hippocampal GABAA receptors are believed to contain a 2 or 3 subunit, because the subunit is thought to be a required subunit for receptor function, and 1 has negligible expression in the hippocampus (Persohn et al., 1992; Sperk et al., 1997).”

“Specifically, when 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).”

“TNF is a proinflammatory cytokine that has been implicated in playing an important role in the neuronal damage caused by a variety of brain insults, such as stroke and head trauma, as well as that which occurs during neurodegenerative disorders (New et al., 1998; Lock et al., 1999; Shohami et al., 1999; Nagatsu et al.…”

“This was evident in both the measurements of mean mEPSC amplitude (82.7 2.4% of initial mEPSC amplitude; n pocampus (Persohn et al., 1992; Sperk et al., 1997).”

“These findings, as well as previous reports (Tancredi et al., 1992; Grassi et al., 1994; Emch et al., 2000), suggest that TNF can have significant effects on neural circuit function.”

“In addition, there is evidence that it also plays an important role in normal neural circuit development and function (Pan et al., 1997; Vitkovic et al., 2000; Beattie et al., 2002; Neumann et al., 2002; Perry et al., 2002; Golan et al., 2004).”

“Thus, similar to the actions of insulin and glycine on cultured neurons (Passafaro et al., 2001; Man et al., 2003), the increase in AMPAR surface expression attributable to TNF appears to require PI3K activity.”

“It has become clear, however, that many immune molecules may be used constitutively by the CNS as signaling molecules involved in intercellular communication (Pan et al., 1997; Vitkovic et al., 2000; Perry et al., 2002; Golan et al., 2004).”

“Many of the newly exocytosed AMPARs lacked or had lower stoichiometric amounts of GluR2, as evidenced by their sensitivity to HPP-spermine (Washburn et al., 1997; Dingledine et al., 1999).”

“Furthermore, immune molecules such as cytokines are also thought to importantly contribute to the brain damage induced by a wide variety of neuronal insults as well as neurodegenerative diseases (New et al., 1998; Lock et al., 1999; Shohami et al., 1999; Nagatsu et al., 2000; Perry et al., 2001; Szelenyi, 2001), while…”

“Using an antibody to the GABAA receptor 2/3 subunit (Richards et al., 1987), there was no increase in the level of surface expression of GABAA receptors after 15 min of TNF treatment compared with untreated cultures, despite a nearly twofold increase in the surface AMPARs that were measured in the…”

“…insults as well as neurodegenerative diseases (New et al., 1998; Lock et al., 1999; Shohami et al., 1999; Nagatsu et al., 2000; Perry et al., 2001; Szelenyi, 2001), while also having some neuroprotective functions in certain circumstances (MorgantiKossmann et al., 2002; Stoll et al., 2002).”

“…AMPARs, a change in their stoichiometry to make them Ca 2 permeable, and a decrease in inhibition, all will enhance the excitotoxicity that accompanies neuronal insults and some autoimmune and neurodegenerative diseases that may involve TNF (Epstein and Gelbard, 1999; Weiss and Sensi, 2000).”

“Cytokines and cytokine receptor materials were from R & D Systems (Minneapolis, MN), except the TNFR2 activating antibodies, which were from Abcam (Cambridge, MA).”

“, 2001), and increasing the proportion of calcium-permeable AMPARs greatly increases neuronal vulnerability (Feldmeyer et al., 1999; Oguro et al., 1999).”

“…of TNF to neural injury are likely, at least in part, attributable to its ability to potentiate glutamate excitotoxicity (Gelbard et al., 1993; Chao and Hu, 1994; New et al., 1998; Epstein and Gelbard, 1999; Hermann et al., 2001), which importantly contributes to much of the secondary damage…”

“Indeed, a number of neuronal insults, including hypoxia, ischemia, epileptiform activity, and spinal cord contusions, show an increase in non-GluR2-containing AMPARs (Ying et al., 1997; Grossman et al., 1999; Grooms et al., 2000; Sanchez et al., 2001), and increasing the proportion of calcium-permeable AMPARs greatly…”

“…attributable to its ability to potentiate glutamate excitotoxicity (Gelbard et al., 1993; Chao and Hu, 1994; New et al., 1998; Epstein and Gelbard, 1999; Hermann et al., 2001), which importantly contributes to much of the secondary damage after brain insults (Choi, 1994; Wrathall et al., 1994).”

“It has become clear, however, that many immune molecules may be used constitutively by the CNS as signaling molecules involved in intercellular communication (Pan et al., 1997; Vitkovic et al., 2000; Perry et al., 2002; Golan et al., 2004).”

“…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).”

“…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).”

“…are also thought to importantly contribute to the brain damage induced by a wide variety of neuronal insults as well as neurodegenerative diseases (New et al., 1998; Lock et al., 1999; Shohami et al., 1999; Nagatsu et al., 2000; Perry et al., 2001; Szelenyi, 2001), while also having some…”

“…attributable to its ability to potentiate glutamate excitotoxicity (Gelbard et al., 1993; Chao and Hu, 1994; New et al., 1998; Epstein and Gelbard, 1999; Hermann et al., 2001), which importantly contributes to much of the secondary damage after brain insults (Choi, 1994; Wrathall et al., 1994).”

“…pathological contributions of TNF to neural injury are likely, at least in part, attributable to its ability to potentiate glutamate excitotoxicity (Gelbard et al., 1993; Chao and Hu, 1994; New et al., 1998; Epstein and Gelbard, 1999; Hermann et al., 2001), which importantly contributes to much of…”

“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).”

“Consistent with a primary role for TNFR1 in mediating the effects of TNF on AMPARs, stimulation of TNFR1 alone using an activating antibody for 15 min (Diem et al., 2001) caused a clear increase in the surface expression of AMPARs (257 15% of untreated cells; n 81) (Fig.”

“Indeed, a number of neuronal insults, including hypoxia, ischemia, epileptiform activity, and spinal cord contusions, show an increase in non-GluR2-containing AMPARs (Ying et al., 1997; Grossman et al., 1999; Grooms et al., 2000; Sanchez et al., 2001), and increasing the proportion of calcium-permeable AMPARs greatly…”

“, 2001), and increasing the proportion of calcium-permeable AMPARs greatly increases neuronal vulnerability (Feldmeyer et al., 1999; Oguro et al., 1999).”

“…including hypoxia, ischemia, epileptiform activity, and spinal cord contusions, show an increase in non-GluR2-containing AMPARs (Ying et al., 1997; Grossman et al., 1999; Grooms et al., 2000; Sanchez et al., 2001), and increasing the proportion of calcium-permeable AMPARs greatly increases…”

“The findings presented here, specifically an increase in surface AMPARs, a change in their stoichiometry to make them Ca 2 permeable, and a decrease in inhibition, all will enhance the excitotoxicity that accompanies neuronal insults and some autoimmune and neurodegenerative diseases that may involve TNF (Epstein and…”

“TNF may also increase the size of the pool of non-GluR2-containing AMPARs, because 24 h treatment with TNF has been reported to increase the expression of GluR1, but not other AMPAR subunits, in a neuronal cell line (Yu et al., 2002).”

“These findings, as well as previous reports (Tancredi et al., 1992; Grassi et al., 1994; Emch et al., 2000), suggest that TNF can have significant effects on neural circuit function.”

“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.”

“…neuronal insults, including hypoxia, ischemia, epileptiform activity, and spinal cord contusions, show an increase in non-GluR2-containing AMPARs (Ying et al., 1997; Grossman et al., 1999; Grooms et al., 2000; Sanchez et al., 2001), and increasing the proportion of calcium-permeable AMPARs…”

“These findings, as well as previous reports (Tancredi et al., 1992; Grassi et al., 1994; Emch et al., 2000), suggest that TNF can have significant effects on neural circuit function.”

“…induced by a wide variety of neuronal insults as well as neurodegenerative diseases (New et al., 1998; Lock et al., 1999; Shohami et al., 1999; Nagatsu et al., 2000; Perry et al., 2001; Szelenyi, 2001), while also having some neuroprotective functions in certain circumstances…”

“…an important role in the neuronal damage caused by a variety of brain insults, such as stroke and head trauma, as well as that which occurs during neurodegenerative disorders (New et al., 1998; Lock et al., 1999; Shohami et al., 1999; Nagatsu et al., 2000; Perry et al., 2001; Szelenyi, 2001).”

“Furthermore, the TNF -induced increase in the surface expression of AMPARs may contribute significantly to its putative role in mediating the brain damage resulting from a variety of pathological insults (Gelbard et al., 1993; Chao and Hu, 1994; Le et al., 1997; Hermann et al., 2001).”

“Specifically, secretion of the proinflammatory cytokine tumor necrosis factor-a from glial cells appears to be necessary for the increase in the level of synaptic AMPARs caused by extended periods of activity blockade (Beattie et al, 2002; Stellwagen et al, 2005; Stellwagen and Malenka, 2006).”

“The pro-inflammatory cytokine tumour necrosis factor-&alpha”