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Exp Physiol 90.5 pp 663670

Experimental Physiology Hot Topic Review

Actions of TNF- on glutamatergic synaptic transmission

in the central nervous system
Mark Pickering, Derval Cumiskey and John J. OConnor
Department of Human Anatomy and Physiology, Conway Institute of Biomolecular and Biomedical Research, University College Dublin,
Belfield, Dublin 4, Ireland

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 00 Month 2005)
Corresponding author J. J. OConnor: Department of Human Anatomy and Physiology, Conway Institute of
Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland.
Email: john.oconnor@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 bloodbrain
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


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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.
In the context of this review, it is probably most
relevant to note that the signal transduction pathway
DOI: 10.1113/expphysiol.2005.030734

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M. Pickering and others

used by the p55 TNF-R1 can result in the activation

of the transcription factor nuclear factor kappa B (NFB) (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 (ONeill &
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

Figure 1. Schematic diagram of some of the relevant TNF-R

signalling pathways
TNF- binds to both TNF-R1 and TNF-R2 on the cell membrane. Both
receptors activate tumour necrosis factor associated factor 2 (TRAF2),
which causes the activation of the transcription factors activator
protein 1 (AP1) via Jun N-terminal kinase (JNK) and NF-B via
NF-B-inducing kinase (NIK). While both receptors activate this
signalling pathway, only TNF-R1 activation leads to activation of
caspases and ceramide which can lead to apoptosis.

Exp Physiol 90.5 pp 663670

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 -amyloid-induced microglia-related
cell death. Abundant activated microglia are prominent
in the brains of Alzheimer patients (Griffin et al. 1989)


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Exp Physiol 90.5 pp 663670

TNF- and glutamate in the CNS

and are associated with -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 Alzheimers disease. By applying
media from -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-laspartyl-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).
Glialglial 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 glialglial and glialneuronal
interactions, it is possible to see how a cascading
glialneuronal 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.


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TNF- and glutamatergic synaptic transmission

The subject of TNF- in glialneuronal 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 longterm treatment (2448 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
4050%, whereas the N- and Q-type currents showed
increases of 1025%. 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.

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M. Pickering and others

(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

Figure 2. The p38 MAP kinase inhibitor SB 203580 reverses

early- but not late-phase-mediated inhibition of LTP by TNF-
A, SB 203580 (1 M) was added at time 10 min, TNF- (4.5 ng ml1 )
at time 40 min, and high frequency stimulation (HFS) was delivered to
the slice at time 60 min. SB 203580 reversed the inhibitory effect of
TNF- 1 h post tetanus (174 5%, versus 120 7%, n = 6;
P < 0.001). At 3 h post tetanus SB 203580 had a reduced but highly
significant antagonistic effect on TNF--mediated depression of LTP. B,
comparison of slices treated with TNF- in the presence of SB 203580
(as A) to control LTP. The rectangles represent the period of perfusion
of the designated cytokine/drug. HFS is represented by the arrow.
Figure reprinted from Butler et al. (2004). Neuroscience, 124,
319326, copyright (2004) with permission from Elsevier.

Exp Physiol 90.5 pp 663670

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 longterm depression (LTD), involve glutamate receptor
activation and increased intracellular calcium levels,
with induction of LTP dependent on the activation of
calciumcalmodulin 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 1 (Cunningham et al. 1996; Curran et al.
2003) and interleukin 18 (Curran & OConnor, 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.

Figure 3. Schematic diagram of the putative role of the mGluR

and TNF-R in long-term potentiation
TNF- inhibits the early phase of LTP by activation of TNF-R1 (p55) and
is dependent on p38 activation. Additionally, TNF- causes an increase
in NF-B, which may lead to inhibition of late LTP by an as yet
unknown mechanism. Activation of the G-protein-linked mGluRs leads
to inositol-1,4,5-trisphosphate (IP3 ) receptor-mediated calcium release
via phospholipase C (PLC). TNF- may also alter calcium
concentrations. Combined activation of TNF-R1 and mGluRs may lead
to sufficiently high calcium concentrations to impair the formation of
LTP, although the exact nature of the interaction between TNF-R1 and
mGluR activation remains unknown.


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TNF- and glutamate in the CNS

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.
It has also been shown that application of TNF-
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 G i 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).
If the TNF--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- NFB 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


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667

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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