Synaptic NMDA receptor activity boosts intrinsic antioxidant defenses

被引：412

作者：

Papadia, Sofia ^{[1
]}

Soriano, Francesc X. ^{[1
]}

Leveille, Frederic ^{[1
]}

Martel, Marc-Andre ^{[1
]}

Dakin, Kelly A. ^{[2
]}

Hansen, Henrik H. ^{[3
]}

Kaindl, Angela ^{[4
,5
]}

Sifringer, Marco ^{[3
]}

Fowler, Jill ^{[1
]}

Stefovska, Vanya ^{[3
]}

Mckenzie, Grahame ^{[6
]}

Craigon, Marie ^{[7
]}

Corriveau, Roderick ^{[8
]}

Ghazal, Peter ^{[7
]}

Horsburgh, Karen ^{[1
]}

Yankner, Bruce A. ^{[2
]}

Wyllie, David J. A. ^{[1
]}

Ikonomidou, Chrysanthy ^{[3
]}

Hardingham, Giles E. ^{[1
,9
]}

机构：

[1] Univ Edinburgh, Neurosci Res Ctr, Edinburgh EH8 9XD, Midlothian, Scotland

[2] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA

[3] Tech Univ Dresden, Dept Pediat Neurol, D-01307 Dresden, Germany

[4] Charite, Dept Pediat Neurol, D-13353 Berlin, Germany

[5] Hop Robert Debre, Lab Neurol Dev, INSERM, U676, F-75019 Paris, France

[6] Hutchison MRC Res Ctr, MRC Canc Cell Unit, Cambridge CB2 0XZ, England

[7] Univ Edinburgh, Div Pathway Med, Edinburgh EH16 4SB, Midlothian, Scotland

[8] Coriell Inst Med Res, Camden, NJ 08103 USA

[9] Univ Edinburgh, Royal Dick Sch Vet Studies, Edinburgh EH9 1QH, Midlothian, Scotland

来源：

NATURE NEUROSCIENCE | 2008年 / 11卷 / 04期

基金：

英国惠康基金; 英国生物技术与生命科学研究理事会; 英国医学研究理事会;

关键词：

D O I：

10.1038/nn2071

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

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/EBP beta 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.

引用

页码：476 / 487

页数：12

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