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Hot Topic Review |
on glutamatergic synaptic transmission in the central nervous system
1 Department of Human Anatomy and Physiology, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland
Abstract
Increasing attention is being paid to the role of inflammatory and immune molecules in the modulation of central nervous system (CNS) function. Tumour necrosis factor-
(TNF-) is a pro-inflammatory cytokine, the receptors for which are expressed on neurones and glial cells throughout the CNS. Through the action of its two receptors, it has a broad range of actions on neurones which may be either neuroprotective or neurotoxic. It plays a facilitatory role in glutamate excitotoxicity, both directly and indirectly by inhibiting glial glutamate transporters on astrocytes. Additionally, TNF- has direct effects on glutamate transmission, for example increasing expression of AMPA receptors on synapses. TNF- also plays a role in synaptic plasticity, inhibiting long-term potentiation (LTP), a process dependent on p38 mitogen activated kinase (p38 MAP) kinase. In the following review we look at these and other effects of TNF- in the CNS.
(Received 4 May 2005;
accepted after revision 7 June 2005; first published online 14 September 2005)
Corresponding author J. J. O'Connor: Department of Human Anatomy and Physiology, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland. Email: john.oconnor{at}ucd.ie
For many decades the general consensus was that the immune and central nervous systems were relatively independent due to the inaccessibility of the brain to the immune cells because of the blood–brain barrier. This outlook has changed in recent years as it has become apparent that many immune molecules may be used by the nervous system in intercellular communication (Boulanger et al. 2001; Chun, 2001). This review addresses one such immune molecule, tumour necrosis factor- (TNF-) in relation to its role in neurotoxicity, synaptic transmission and synaptic plasticity.
The pro-inflammatory cytokine TNF- is a 17-kDa peptide and forms multimers, which are active in binding TNF- receptors that are constitutively expressed on both neurones and glia in the central nervous system (Benveniste & Benos, 1995). TNF- can be synthesized and released in the brain by astrocytes, microglia and some neurones (Lieberman et al. 1989; Chung & Benveniste, 1990; Morganti-Kossman et al. 1997). Brain TNF- levels are typically increased in a wide range of CNS disorders, including trauma (Goodman et al. 1990), ischaemia (Liu et al. 1994) and multiple sclerosis (Rieckmann et al. 1995). Under such pathological conditions, the expression and release of TNF- is rapid and in some cases as early as 1 h after the brain insult and well before neuronal death (Liu et al. 1994; Wang et al. 1994; Allan & Rothwell, 2001).
Two different receptors for TNF- (p55, or TNF-R1 and p75, or TNF-R2) have been identified (Beutler & Van Huffel, 1994a,b; Wajant & Scheurich, 2001) and shown to mediate differential cellular responses using distinct pathways (Kinouchi et al. 1991; Tartaglia et al. 1991). These receptors have been shown to exist to varying degrees in the brainstem, cortex, cerebellum, thalamus and basal ganglia (Kinouchi et al. 1991). The TNF-R1 and TNF-R2 are present in both neurones and glia (Boka et al. 1994). The pathways activated by TNF-R1 and TNF-R2 are diverse, and include G-protein-mediated activation of protein kinase A (PKA), phospholipase C and phospholipase A2, activation of the sphingomyelinase pathway, production of nitric oxide and ceramide, free radical formation and phosphorylation of other membrane receptors by protein kinases (Kronke et al. 1990; Rothe et al. 1992; Beyaert & Fiers, 1994). The pathways activated by the two receptors are summarized in Fig. 1. Note that while either receptor can lead to the activation of transcription factors, only TNF-R1 activation can lead to activation of the caspase pathways leading to apoptosis.
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B) (Kolesnick & Golde, 1994; Goodman & Mattson, 1996; Mattson et al. 1997a,b), which is pivotal in controlling diverse cellular processes, including immune responses, cell proliferation and differentiation (Israel, 2000; Silverman & Maniatis, 2001; Ghosh & Karin, 2002; Li & Verma, 2002). Increasingly, it has become evident that NF-B also plays important roles in the CNS (O'Neill & Kaltschmidt, 1997).
A role for TNF- in glutamate neurotoxicity
Although TNF- was originally named for its degeneration-inducing action in some types of tumour cells, the relationship between TNF- and cell toxicity and death is not a simple one. On the one hand, TNF- has been shown to induce cell death in septo-hippocampal cultures. Zhao et al. (2001) detected -spectrin fragments in these septo-hippocampal cultures treated with TNF- and found elevated 120kDa fragments, indicative of caspase-3 activity, but not 145-kDa fragments, indicative of calpain activity. Unlike calpain, which is associated with both necrotic and apoptotic cell death, caspase-3 is exclusively characteristic of apoptosis-like cell death (Armstrong et al. 1996; Wang et al. 1996; Nath et al. 1998).
On the other hand, a number of investigators have presented evidence that, under different conditions, TNF- may play a protective role against neuronal cell death. For example, while it has been shown that TNF- mediates damage to myelin and oligodendrocytes (Selmaj & Raine, 1998), Garcia et al. (1992) found that it was not toxic to rat cultured CNS neurones. TNF- under in vitro conditions may protect neurones against metabolic, excitotoxic or oxidative insults by promoting maintenance of intracellular calcium homeostasis, suppression of reactive oxygen species (Cheng et al. 1994), and by activation of transcription factor NF-B (Barger et al. 1995). Mice genetically deficient in TNF-R1 or both TNF-R1 and TNF-R2, also show exacerbated neuronal damage compared to wild-type controls following middle cerebral artery occlusion (Bruce et al. 1996; Gary et al. 1998).
Another aspect of this complexity may relate to the role of TNF- in the interactions between neurones and glia. Increasingly glial cells are no longer seen as passive supporters of neurones, but as active participants in information processing (for review see Haydon, 2001; Volterra & Steinhauser, 2004). Of particular interest is the relationship between neurones, glial cells and TNF- in glutamate excitotoxicity.
Excitotoxicity in general is linked to excessive glutamate activation of receptors, particularly the N-methyl-D-aspartate (NMDA) receptor. Cell death resulting from excessive levels of glutamate and over stimulation of glutamate receptors is known to be caused by impaired uptake of glutamate by glial cells (Choi, 1988). In vivo, it has been shown that mice lacking expression of the excitatory amino acid transporter, EAAT2/GLT-1 develop epilepsy and increased susceptibility to acute injury as a result of excessive extracellular glutamate levels (Tanaka et al. 1997). The expression of this transporter has been shown recently to be both positively and negatively regulated by NF-B (Sitcheran et al. 2005). This study showed that the increased binding of NF-B to the EAAT2 promoter in H4 astroglioma cells was regulated by epidermal growth factor (EGF), but decreased expression was caused by TNF- inducing the classical I kappa B (IB) degradation pathway to trigger NF-B nuclear translocation and DNA binding to repress EAAT2 expression. In this situation, the presence of elevated TNF- concentrations leads to elevated extracellular glutamate concentration, thereby increasing the risk of glutamate excitotoxicity. Hermann et al. (2001) were the first to demonstrate that the combination of glutamate and TNF- provoked an amplified neurotoxic effect that was contingent on the AMPA receptor. Interestingly, Zou & Crews (2005) showed that in rat organotypic hippocampal slice cultures, which possess a cytoarchitecture comparable to that in vivo, TNF- increased glutamate neurotoxicity. They also demonstrated that the effect was mediated by NMDA and not AMPA receptors.
In addition to this, TNF- and glutamate have also been implicated in ß-amyloid-induced microglia-related cell death. Abundant activated microglia are prominent in the brains of Alzheimer patients (Griffin et al. 1989) and are associated with ß-amyloid plaques (Griffin et al. 1995; Frautschy et al. 1998). It has been proposed that inefficient phagocytosis of peptide by microglia could lead to hyperactivation of cells and release of inflammatory mediators and neurotoxic factors, thereby contributing to neurodegenerative processes (Akiyama et al. 2000). It is widely believed that the microglia play a direct role in the neuronal death seen in Alzheimer's disease. By applying media from ß-amyloid-stimulated microglial cultures to neurones, Floden et al. (2005) showed that neuronal cell death is dependent on the synergistic co-activation of TNF- and NMDA receptors; the NMDA receptor antagonists memantine and 2-amino-5-phosphopetanoic acid, as well as soluble TNF- receptor applied to the neurones, protected them from cell death. It is interesting that blockade of either the TNF- receptor or the NMDA receptor alone was insufficient to induce neuronal cell death.
There is, however, evidence that other glutamate receptors are involved in the relationship between neuronal cell death, glial cells and TNF-. Taylor et al. (2005) examined the effect of metabotropic glutamate receptor (mGluR) stimulation on TNF- release. They found that stimulating rat primary cultured microglial mGluRs for 24 h induced microglial activation. This in turn induced caspase-3 activation in cerebellar granule neurones in culture. This neurotoxicity was mediated by TNF- released by the microglia via neuronal TNF-R1 and caspase-3 activation (Fig. 1). Importantly, it was the specific group II mGluR agonist 2S,2'R,3'R-2-(2',3'-dicarboxycyclopropyl)glycine that led to the release of TNF- and the consequent toxicity. N-acetyl-L-aspartyl-L-glutamate, a specific mGluR3 agonist, did not induce microglial activation or neurotoxicity. TNF- was only neurotoxic in the presence of microglia or conditioned medium from microglia, a fact possibly due to the presence of microglial-derived Fas ligand. However, TNF--dependent neurotoxicity was prevented when the neurones were exposed to conditioned medium from microglia stimulated by the specific group III agonist L-2-amino-4-phosphono-butyric acid (Taylor et al. 2005).
Glial–glial interactions also play a role in this system. Bezzi et al. (2001) showed that astrocyte glutamate release induced by activation of the chemokine receptor CXCR4 is accompanied by release of TNF-, and that the TNF- release is dramatically enhanced by microglia. In light of this evidence of glial–glial and glial–neuronal interactions, it is possible to see how a cascading glial–neuronal interaction could occur, leading to cell death. Activation of TNF- receptors on astrocytes leads to increased extracellular glutamate concentration, which may lead to neurotoxicity in itself, while also activating mGluR2 on microglia, which release more TNF- in addition to other pro-inflammatory cytokines.
TNF- and glutamatergic synaptic transmission
The subject of TNF- in glial–neuronal interactions also emerges when looking at glutamatergic synaptic transmission. Beattie et al. (2002) showed that glial TNF- causes an increase in surface expression of neuronal AMPA receptors, thereby increasing synaptic efficacy. Indeed, they showed that removal of endogenous TNF- had a negative effect on AMPA receptor expression. It has recently been shown that this AMPA receptor exocytosis is mediated by activation of TNF-R1 through a phosphatidylinositol 3-kinase (PI3)-dependent pathway (Stellwagen et al. 2005). The newly expressed AMPA receptors were shown to have lower stoichiometric amounts of GluR2, making the receptors permeable to calcium ions. Additionally, this study also showed a surprising concurrent endocytosis of inhibitory GABA receptors induced by TNF-. Furukawa & Mattson (1998) presented further evidence that TNF- alters glutamatergic transmission and neuronal excitability. They showed, using whole-cell perforated patch-clamp recording of cultured hippocampal neurones, that long-term treatment (24–48 h) with TNF- caused an increase in calcium current by 
30%. Selective blockade of calcium channel showed that this increase was largely due to L-type calcium channels, whose currents increased by 40–50%, whereas the N- and Q-type currents showed increases of 10–25%. They measured the actual calcium concentrations using fluorescence imaging and showed that while 24-h TNF- exposure did not alter resting intracellular calcium concentration, it did increase the elevated calcium concentration caused by 50 mM KCl depolarization.
Furukawa & Mattson (1998) also showed that whole-cell currents in these cultured hippocampal neurones induced by glutamate, NMDA, AMPA and kainite were decreased by 24-h exposure to TNF-. In addition, fluorescence calcium imaging was used to show that the increase in intracellular calcium concentration caused by application of glutamate receptor agonists was decreased after 24-h TNF- exposure. NF-B was also shown to be important in regulating these responses to TNF-; no effect was seen in response to shorter exposure to TNF-, on a timescale suggesting possible altered gene expression, and the effect of TNF- was abolished by co-treatment with decoy DNA (Furukawa & Mattson, 1998). The difference between calcium responses to depolarization and glutamate receptor activation suggests that the effect of TNF- is more complex than simply altering calcium homeostasis.
The relationship between glutamatergic transmission and TNF- was also examined in the nucleus of the solitary tract. It has been shown that neurones excited by gastric distension in the nucleus of the solitary tract are excited by TNF- (Emch et al. 2000). Emch et al. (2001), using the immediate early gene product c-fos as a marker for neuronal activation, found that c-fos expression in that region, elicited by TNF- injection, was impaired by AMPA and NMDA receptor blockers, suggesting that TNF- activation of these neurones is dependent on altered glutamate neurotransmission resulting from the presence of TNF-.
TNF- and synaptic plasticity
These TNF--induced changes in neuronal excitability may have important implications for synaptic plasticity (Carroll et al. 2001). Indeed, in addition to its role in apoptotic events, TNF- is known to act as a regulator of synaptic plasticity. TNF- levels are elevated in several neuropathological states that are associated with learning and memory deficits, leading to the search for a possible role in plasticity. To this end, much work has been carried out in the hippocampus. TNF- has been shown to regulate the development of the hippocampus, as TNF-R1 and TNF-R2 knockout mice demonstrate decreased arbourization of the apical dendrites of the CA1 and CA3 regions and accelerated dentate gyrus development (Golan et al. 2004), probably via activation of TNF-R2, which, as mentioned earlier, does not lead to caspase-3 activation, but is known to transduce the trophic effect of TNF- (Yang et al. 2002).
The two forms of synaptic plasticity seen in the hippocampus, long-term potentiation (LTP) and long-term depression (LTD), involve glutamate receptor activation and increased intracellular calcium levels, with induction of LTP dependent on the activation of calcium–calmodulin kinase II, protein kinase C (PKC) and PKA, and induction of LTD dependent on activation of serine/threonine phosphatases 1, 2A and 2B (Mayford et al. 1995; Coussens & Teyler, 1996; Silva et al. 1997). LTP is a long-lasting increase in synaptic efficacy, which is thought to be an important underlying mechanism of learning and memory formation (Bliss & Collingridge, 1993).
Several pro-inflammatory cytokines have been shown to act as inhibitors of the induction of LTP, for example interleukin 1ß (Cunningham et al. 1996; Curran et al. 2003) and interleukin 18 (Curran & O'Connor, 2001). Like these other cytokines, TNF- has also been shown to inhibit LTP in the CA1 and dentate gyrus regions of the rat hippocampus at pathophysiological levels (Tancredi et al. 1992; Cunningham et al. 1996; Butler et al. 2004). However there would appear to be differences in the mechanisms by which TNF- inhibits early phase (less than 2 h) and late phase LTP (greater than 2 h post induction (Butler et al. 2004). Using electrophysiological and immunohistological techniques it was found that there was a major role played by the p38 MAP kinase in the inhibitory effect of TNF- on early LTP (Butler et al. 2004; Fig. 2). The p38 inhibitor SB 203580 reversed the effect of TNF- on early LTP without affecting late LTP.
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causes an increase in RGS7 (a regulator of G-protein signalling), and that this increase is dependent on activation of p38 MAP kinase (Benzing et al. 2002). The RGS7 protein modulates G-protein signalling by accelerating the intrinsic GTPase activity of Gi and Gq subunits. Increased RGS7 levels therefore leads to increased Gq levels, giving rise to increased calcium levels. Combined with the aforementioned evidence from Stellwagen et al. (2005) that TNF- causes increased expression of AMPA receptors which may be more calcium permeable, the intracellular calcium concentrations may become sufficiently elevated in the presence of TNF- to contribute to the impairment of LTP.
mGLuRs may also play a role in the inhibitory effects of TNF- on early LTP. We have recently shown that inhibition of mGluR1 and mGluR5 can block the TNF--dependent inhibition of early and late LTP (Cumiskey et al. 2004). Activation of these subtypes of mGluRs would also lead to an increase in intracellular calcium concentration. Thus a complex and as yet undiscovered interaction between TNF- and mGlu receptors and the p38 MAP kinase would be required for inhibition of LTP to occur (Fig. 3).
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-dependent inhibition of the early stage of LTP is mediated by a p38 MAP kinase pathway and activation of mGluRs, then it may be that the late phase inhibition of LTP by TNF- is regulated by altered protein synthesis (Frey et al. 1993; Huang & Kandel, 1994; Nguyen & Kandel, 1996). Exactly how TNF- might interfere with new protein synthesis in LTP remains to be elucidated, but a likely candidate is the transcription factor, NF-B (Butler et al. 2002; Fig. 3).
In addition to the effect of TNF- on LTP, it has been shown that TNF-?receptor knockout mice demonstrate an impairment of LTD in the CA1 region of the hippocampus (Albensi & Mattson, 2000). The effect is mimicked by kappa B (B) decoy DNA, which implicates the TNF- NF–B signalling pathway in LTD as well as LTP.
It is interesting that the findings relating to the effect of TNF- on synaptic plasticity seems to have some behavioural correlates in vivo. TNF- knockout mice showed increased performance in spatial memory and learning as measured in the Morris water maze task when compared to wild-type animals (Golan et al. 2004). Conversely, Aloe et al. (1999) demonstrated a significant impairment in spatial learning in two lines of mice that over-expressed human recombinant TNF-, also using the same water maze task. However, these results must be interpreted in the context of the study showing developmental differences mentioned previously; the ‘substrate’ of learning and memory cannot be seen as the same in the knockout and wild-type mice.
Concluding remarks
While undoubtedly recent work has greatly expanded our knowledge of the role of the interactions between the pro-inflammatory cytokine, TNF- and glutamate in the CNS, a great many questions remain unanswered. Inflammatory and immunological challenges, which lead to the increase in TNF- in the CNS, will normally lead to a coincident increase in other inflammatory mediators. The complexity of the interactions between these mediators should not be underestimated. It is not unlikely that as more information about TNF- and other inflammatory and immunological mediators active in the CNS becomes available, interactions between these agents may manifest as either synergistic or occlusive effects, due to convergent or complimentary intracellular signalling pathways and intercellular interactions. With this in mind, it is unlikely that a full understanding of the roles of TNF- and glutamate in the CNS can be achieved until they can be viewed in the context of a better understanding of the neuroimmunological system.
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