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

Abstract

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.