TNFα in synaptic function: switching gears

Pathological brain states are known to induce massive production of proinflammatory cytokines, including tumor necrosis factor alpha (TNF alpha). At much lower levels, these cytokines are also present in the healthy brain, where it is increasingly being recognized that they exert regulatory influences. Recent studies suggest that TNF alpha plays important roles in controlling synaptic transmission and plasticity. Here, we discuss the evidence in support of synaptic regulation by TNF alpha and the underlying cellular mechanisms, including control of AMPA receptor trafficking and glutamate release from astrocytes. These findings suggest that increases in TNF alpha levels (caused by nervous system infection, injury, or disease) transform the physiological actions of the cytokine into deleterious ones. This functional switch may contribute to cognitive alterations in several brain pathologies.