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/EBPβ 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.
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We thank P. Brophy for critically reading the manuscript and acknowledge J. Stuwe's assistance. We also thank D. Bennett and the Rush Alzheimer's Disease Center (US National Institutes of Health grant P30AG10161) for providing some of the brain samples used in this study and thank D. Accili, H. Bading, J.-C. Chambard, R. Lee, C. Vinson, G. Wilding and J. Yodoi for plasmids. This work was funded by the Wellcome Trust, a Royal Society University Research Fellowship (G.E.H.), Medical Research Scotland, Tenovus Scotland, the Biotechnology and Biological Sciences Research Council, Sanitaetsrat Dr. Emil Alexander Huebner and Gemahlin-Stiftung, a Rahel Hirsch scholarship from the Humboldt University Berlin, and the Network of European Neuroscience Institutes.
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Survival of glioblastoma cells in response to endogenous and exogenous oxidative challenges: possible implication of NMDA receptor‐mediated regulation of redox homeostasis
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