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-α (TNF-α) 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-α has direct effects on glutamate transmission, for example increasing expression of AMPA receptors on synapses. TNF-α 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-α in the CNS.

Pro-inflammatory cytokines are known to be elevated in several neuropathological states that are associated with learning and memory. We have previously demonstrated in our laboratory that the inhibition of long-term potentiation (LTP) in the dentate gyrus region of the rat hippocampus, by tumor necrosis factor (TNF)-α, represents a biphasic response, an early phase dependent on p38 mitogen activated protein kinase (MAPK) activation and a later phase, possible dependent on protein synthesis. Many of the factors involved in the early modulation of LTP by TNF-α have yet to be elucidated. This study investigated if metabotropic glutamate receptors (mGluRs) are functionally linked to the inhibitory effect of TNF-α on LTP in the rat dentate gyrus in vitro. We report that the impairment of early-LTP by TNF-α is significantly attenuated by prior application of the group I/II mGluR antagonist MCPG and more specifically the mGluR5 antagonist MPEP. Since TNF-α is now known to cause transient increases in intracellular Ca 2+ levels from ryanodine-sensitive stores, we explored the possibility that disruption of intracellular Ca 2+ homeostasis could be involved.Ryanodine was found to significantly reverse the inhibition of LTP by TNF-α. From these studies we propose that the TNF-α inhibition of LTP is dependent upon the activation of TNFR1 and mGlu5-receptors. Importantly this study provides the first proof of the involvement of ryanodine-sensitive intracellular Ca 2+ stores in TNF-α mediated inhibition of LTP. IntroductionThe pro-inflammatory cytokine tumor-necrosis factor (TNF)-α is elevated in the brain in a number of neuropathological states including trauma, ischemia, Parkinson's disease, multiple sclerosis and HIV-associated dementia (Iida et al., 2000;Kassiotis and Kollias, 2001;Sriram et al., 2002). The signaling mechanism underlying the ability of TNF-α to cause the cognitive dysfunction associated with many of these conditions has been probed, but to date no clear mechanistic understanding has been reached. TNF-α and IL-1β at pathophysiological levels have been shown by many authors to inhibit long-term potentiation (LTP) in the CA1 and the dentate gyrus regions of the rat hippocampus (Cunningham et al., 1996;Murray and Lynch, 1998;Tancredi et al., 1992) but not by others (Stellwagen and Malenka, 2006). IL-1β has been shown to depress NMDAreceptor mediated field potentials in the dentate gyrus (Coogan B R A I N R E S E A R C H 1 1 3 6 ( 2 0 0 7 ) 1 3 -1 9 ⁎ Corresponding author.

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