Actions of TNF‐α on glutamatergic synaptic transmission in the central nervous system

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-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.

TNF Alpha and Fas Mediate Tissue Damage and Functional Outcome after Traumatic Brain Injury in Mice

“…Tumor necrosis factor-alpha and other cytokines have been postulated to impair learning and memory in a number of neuropathological conditions including CCI (Pickering et al, 2005;Scherbel et al, 1999), and to play a physiological role in normal brain function by modulating key elements of synaptic transmission involved in memory formation and learning (Albensi and Mattson, 2000). Mice with non-functional Fas on the MRL background have spatial learning deficits associated with autoimmunity and brain mononuclear infiltrates (Sakic et al, 1997); however, direct evidence that Fas participates in physiological or pathological learning and memory has not, to our knowledge, been reported.…”

Pharmacological Induction of Ischemic Tolerance by Glutamate Transporter-1 (EAAT2) Upregulation

“…TNF-␣ also has direct effects on glutamate transmission, such as by increasing the expression of AMPA receptors on synapses. 23 In addition, we previously presented evidence that NMDA blocker can reduce endogenous tissue plasminogen activator (tPA) and MMP-9 expressions. 11 In the present study, we found that GLT-1 upregulation reduced the expressions of TNF-␣, FasL, and MMP-9.…”

MAPK-activated Protein Kinase 2 Deficiency in Microglia Inhibits Pro-inflammatory Mediator Release and Resultant Neurotoxicity

“…A large body of evidence describes neurotoxic roles for TNF-␣ within the CNS (48 -50), as well as its ability to affect long-term potentiation and learning (51)(52). For chemokines such as MIP-1␣ and KC, it is likely that their production by plaque-surrounding cells results in the recruitment and accumulation of astrocytes and microglia in an attempt to phagocytose the plaque, thereby creating a vicious cycle of inflammation resulting in a chronic glial inflammation and ultimately neurodegeneration.…”