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

Javier H. Jara, Brij B. Singh, Angela M. Floden, Colin K. Combs

Research output: Contribution to journalArticlepeer-review

66 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1407-1420
Number of pages14
JournalJournal of neurochemistry
Issue number5
StatePublished - Mar 2007
Externally publishedYes


  • Mitogen-activated protein kinase
  • N-methyl-D-aspartate
  • Neuron death
  • Tumor necrosis factor alpha

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Biochemistry


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