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Synaptic NMDA receptor activity boosts intrinsic antioxidant defenses

Nature Neuroscience volume 11, pages 476–487 (2008)Cite this article

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/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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Figure 1: Synaptic NMDAR activity promotes resistance to oxidative insults and prevents ROS accumulation.
Figure 2: Synaptic activity prevents the overoxidation of Prxs in response to an oxidative insult and negatively regulates the thioredoxin inhibitor Txnip.
Figure 3: Txnip and thioredoxin can regulate neuronal vulnerability to oxidative stress.
Figure 4: Synaptic activity promotes reduction of Prx-SO2/3H and induces neuroprotective expression of the Prx-SO2/3H–reducing genes Sesn2 and Srxn1.
Figure 5: Txnip is a FOXO target gene.
Figure 6: Sesn2 is a C/EBP target gene and Srxn1 is an AP-1 target gene.
Figure 7: Extrasynaptic NMDARs do not promote antioxidative effects.
Figure 8: Memantine, but not NR2B antagonists, discriminates between pro-survival and pro-death NMDAR signaling.
Figure 9: An ischemic episode, followed by reperfusion, induces overoxidation of Prxs.

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Acknowledgements

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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Author notes

  1. Sofia Papadia and Francesc X Soriano: These authors contributed equally to this work.

Authors and Affiliations

  1. Centre for Neuroscience Research, University of Edinburgh, Hugh Robson Building George Square, Edinburgh, EH8 9XD, UK

    Sofia Papadia, Francesc X Soriano, Frédéric Léveillé, Marc-Andre Martel, Jill Fowler, Karen Horsburgh, David J A Wyllie & Giles E Hardingham

  2. Department of Pathology, Harvard Medical School, New Research Building, 77 Avenue Louis Pasteur, Boston, 02115, Massachusetts, USA

    Kelly A Dakin & Bruce A Yankner

  3. Department of Pediatric Neurology, Technical University Dresden, Fetscherstr. 74, Dresden, 01307, Germany

    Henrik H Hansen, Marco Sifringer, Vanya Stefovska & Chrysanthy Ikonomidou

  4. Department of Pediatric Neurology, Charité, University Medicine Berlin, Berlin, 13353, Germany

    Angela Kaindl

  5. Laboratoire de Neurologie du Développement, Inserm-Paris U676, Hôpital Robert Debré, Paris, 75019, France

    Angela Kaindl

  6. Hutchison/MRC Research Centre, MRC Cancer Cell Unit, Hills Road, Cambridge, CB2 0XZ, UK

    Grahame Mckenzie

  7. Division of Pathway Medicine, University of Edinburgh, Chancellor's Building, 49 Little France Crescent, Edinburgh, EH16 4SB, UK

    Marie Craigon & Peter Ghazal

  8. Coriell Institute for Medical Research, 403 Haddon Avenue, Camden, 08103, New Jersey, USA

    Roderick Corriveau

  9. Royal (Dick) School of Veterinary Studies, Summerhall, Edinburgh, EH9 1QH, UK

    Giles E Hardingham

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Contributions

S.P., F.X.S. and F.L. performed in vitro experiments and analysis of some in vivo–derived samples. M.-A.M. performed electrophysiological experiments. K.A.D. analyzed human samples in experiments designed by B.A.Y. H.H.H., M.S., V.S. and R.C. prepared in vivo samples. G.M. created the Txnip-luciferase construct. A.K. performed the two-dimensional carbonyl assays. J.F. and K.H. performed MCA occlusion experiments. M.C. performed the microarray expression analysis under direction from P.G. D.J.A.W. directed and assisted in the design of the electrophysiological experiments and had critical input into the manuscript preparation and project design. C.I. directed and designed in vivo experiments and had critical input into the manuscript preparation. G.E.H. performed some in vitro experiments, conceived and directed the project, and wrote the manuscript.

Corresponding author

Correspondence to Giles E Hardingham.

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Papadia, S., Soriano, F., Léveillé, F. et al. Synaptic NMDA receptor activity boosts intrinsic antioxidant defenses. Nat Neurosci 11, 476–487 (2008). https://doi.org/10.1038/nn2071

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