title: Synaptic NMDA receptor activity boosts intrinsic antioxidant defenses.
abstract: 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.
authors.affiliation: Centre for Neuroscience Research, University of Edinburgh, Hugh Robson Building George Square, Edinburgh EH8 9XD, UK.
authors.forename: Sofia
authors.initials: S
authors.lastname: Papadia
authors.forename: Francesc X
authors.initials: FX
authors.lastname: Soriano
authors.forename: Frédéric
authors.initials: F
authors.lastname: Léveillé
authors.forename: Marc-Andre
authors.initials: MA
authors.lastname: Martel
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Dakin
authors.forename: Henrik H
authors.initials: HH
authors.lastname: Hansen
authors.forename: Angela
authors.initials: A
authors.lastname: Kaindl
authors.forename: Marco
authors.initials: M
authors.lastname: Sifringer
authors.forename: Jill
authors.initials: J
authors.lastname: Fowler
authors.forename: Vanya
authors.initials: V
authors.lastname: Stefovska
authors.forename: Grahame
authors.initials: G
authors.lastname: McKenzie
authors.forename: Marie
authors.initials: M
authors.lastname: Craigon
authors.forename: Roderick
authors.initials: R
authors.lastname: Corriveau
authors.forename: Peter
authors.initials: P
authors.lastname: Ghazal
authors.forename: Karen
authors.initials: K
authors.lastname: Horsburgh
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Yankner
authors.forename: David J A
authors.initials: DJ
authors.lastname: Wyllie
authors.forename: Chrysanthy
authors.initials: C
authors.lastname: Ikonomidou
authors.forename: Giles E
authors.initials: GE
authors.lastname: Hardingham
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology; D051379:Mice; D009474:Neurons / Q000378:metabolism; D009687:Nuclear Proteins; D018384:Oxidative Stress / Q000502:physiology*; D050862:Oxidoreductases Acting on Sulfur Group Donors / Q000378:metabolism; D010544:Peroxidases; D054464:Peroxiredoxins / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013569:Synapses / Q000378:metabolism; D009435:Synaptic Transmission / Q000502:physiology; D013879:Thioredoxins / Q000378:metabolism*; D014158:Transcription, Genetic / Q000502:physiology; D000084622:Sestrins
chemical_list: D000975:Antioxidants; D002352:Carrier Proteins; D009687:Nuclear Proteins; D050862:Oxidoreductases Acting on Sulfur Group Donors; D010544:Peroxidases; D054464:Peroxiredoxins; D011506:Proteins; D016194:Receptors, N-Methyl-D-Aspartate; D013879:Thioredoxins; C445672:Txnip protein, mouse; C529380:Sesn2 protein, mouse; D000084622:Sestrins; C529381:sulfiredoxin protein, mouse