Article abstract
Nature Neuroscience 11, 476 - 487 (2008)
Published online: 23 March 2008 | doi:10.1038/nn2071
Synaptic NMDA receptor activity boosts intrinsic antioxidant defenses
Sofia Papadia1,10, Francesc X Soriano1,10, Frédéric Léveillé1, Marc-Andre Martel1, Kelly A Dakin2, Henrik H Hansen3, Angela Kaindl4,5, Marco Sifringer3, Jill Fowler1, Vanya Stefovska3, Grahame Mckenzie6, Marie Craigon7, Roderick Corriveau8, Peter Ghazal7, Karen Horsburgh1, Bruce A Yankner2, David J A Wyllie1, Chrysanthy Ikonomidou3 & Giles E Hardingham1,9
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/EBP
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.
- Centre for Neuroscience Research, University of Edinburgh, Hugh Robson Building George Square, Edinburgh EH8 9XD, UK.
- Department of Pathology, Harvard Medical School, New Research Building, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA.
- Department of Pediatric Neurology, Technical University Dresden, Fetscherstr. 74, 01307 Dresden, Germany.
- Department of Pediatric Neurology, Charité, University Medicine Berlin, 13353 Berlin, Germany.
- Laboratoire de Neurologie du Développement, Inserm-Paris U676, Hôpital Robert Debré, 75019 Paris, France.
- Hutchison/MRC Research Centre, MRC Cancer Cell Unit, Hills Road, Cambridge CB2 0XZ, UK.
- Division of Pathway Medicine, University of Edinburgh, Chancellor's Building, 49 Little France Crescent, Edinburgh EH16 4SB, UK.
- Coriell Institute for Medical Research, 403 Haddon Avenue, Camden, New Jersey 08103, USA.
- Royal (Dick) School of Veterinary Studies, Summerhall, Edinburgh EH9 1QH, UK.
- These authors contributed equally to this work.
Correspondence to: Giles E Hardingham1,9 e-mail: giles.hardingham@ed.ac.uk
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