Figure 2

Summary of the detrimental effects of TNF-α on both neuronal and glial cells during cerebral ischemia. TNF-α synthesis and release for both neuronal and glial cells may be induced via stimulation of mGlu2R by glutamate. TNF-α may then act in an autocrine and/or paracrine fashion, modulating neuronal and glial signalling. Direct stimulation of the TNFR1-caspase 3 pathway results in inactivation of glial EAAT2s, while activation of the NFkB pathway reduces the synthesis and expression of this glutamate transporter. Upregulation of glutaminase in response to microglial TNFR activation also enhances glutamate synthesis and release, elevating levels of this neurotransmitter in the synapse. TNFR1 signalling may also enhance AMPAR trafficking into the postsynaptic membrane, enhancing the sensitivity of the cells to glutamate. Together, these effects result in the exacerbation of glutamate excitotoxicity during cerebral ischemia.