Synaptic NMDA receptor activity boosts intrinsic antioxidant defenses

Nat Neurosci. 2008 Apr;11(4):476-87. doi: 10.1038/nn2071. Epub 2008 Mar 23.


Intrinsic antioxidant defenses are important for neuronal longevity. We found that in rat neurons, synaptic activity, acting via NMDA receptor (NMDAR) signaling, boosted antioxidant defenses by making changes to the thioredoxin-peroxiredoxin (Prx) system. Synaptic activity enhanced thioredoxin activity, facilitated the reduction of overoxidized Prxs and promoted resistance to oxidative stress. Resistance was mediated by coordinated transcriptional changes; synaptic NMDAR activity inactivated a previously unknown Forkhead box O target gene, the thioredoxin inhibitor Txnip. Conversely, NMDAR blockade upregulated Txnip in vivo and in vitro, where it bound thioredoxin and promoted vulnerability to oxidative damage. Synaptic activity also upregulated the Prx reactivating genes Sesn2 (sestrin 2) and Srxn1 (sulfiredoxin), via C/EBPbeta and AP-1, respectively. Mimicking these expression changes was sufficient to strengthen antioxidant defenses. Trans-synaptic stimulation of synaptic NMDARs was crucial for boosting antioxidant defenses; chronic bath activation of all (synaptic and extrasynaptic) NMDARs induced no antioxidative effects. Thus, synaptic NMDAR activity may influence the progression of pathological processes associated with oxidative damage.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antioxidants / metabolism*
  • Carrier Proteins / metabolism
  • Cells, Cultured
  • Cerebral Cortex / cytology
  • Cerebral Cortex / metabolism
  • Gene Expression Regulation / physiology
  • Mice
  • Neurons / metabolism
  • Nuclear Proteins
  • Oxidative Stress / physiology*
  • Oxidoreductases Acting on Sulfur Group Donors / metabolism
  • Peroxidases
  • Peroxiredoxins / metabolism*
  • Proteins / metabolism
  • Rats
  • Receptors, N-Methyl-D-Aspartate / metabolism*
  • Signal Transduction / physiology
  • Synapses / metabolism
  • Synaptic Transmission / physiology
  • Thioredoxins / metabolism*
  • Transcription, Genetic / physiology


  • Antioxidants
  • Carrier Proteins
  • Nuclear Proteins
  • Proteins
  • Receptors, N-Methyl-D-Aspartate
  • Txnip protein, mouse
  • Thioredoxins
  • Peroxidases
  • Sesn2 protein, mouse
  • Peroxiredoxins
  • Oxidoreductases Acting on Sulfur Group Donors
  • sulfiredoxin protein, mouse