Tumor necrosis factor alpha stimulates NMDA receptor activity in mouse cortical neurons resulting in ERK-dependent death

Multiple cytokines are secreted in the brain during pro-inflammatory conditions and likely affect neuron survival. Previously, we demonstrated that glutamate and tumor necrosis factor alpha (TNFα) kill neurons via activation of the N-methyl-d-aspartate (NMDA) and TNFα receptors, respectively. This report continues characterizing the signaling cross-talk pathway initiated during this inflammation-related mechanism of death. Stimulation of mouse cortical neuron cultures with TNFα results in a transient increase in NMDA receptor-dependent calcium influx that is additive with NMDA stimulation and inhibited by pre-treatment with the NMDA receptor antagonist, dl-2-amino-5-phosphonovaleric acid, or the α-amino-3-hydroxy- 5-methylisoxazole-4-propionate/kainate receptor antagonist, 6,7- dinitroquinoxaline-2,3-dione. Pre-treatment with N-type calcium channel antagonist, ω-conotoxin, or the voltage-gated sodium channel antagonist, tetrodotoxin, also prevents the TNFα-stimulated calcium influx. Combined TNFα and NMDA stimulation results in a transient increase in activity of extracellular signal-regulated kinases (ERKs) and c-Jun N-terminal kinases (JNKs). Specific inhibition of ERKs but not JNKs is protective against TNFα and NMDA-dependent death. Death is mediated via the low-affinity TNFα receptor, TNFRII, as agonist antibodies for TNFRII but not TNFRI stimulate NMDA receptor-dependent calcium influx and death. These data demonstrate how microglial pro-inflammatory secretions including TNFα can acutely facilitate glutamate-dependent neuron death.