Synaptic NMDA receptor activity boosts intrinsic antioxidant defenses

Papadia, Sofia, Soriano, Francesc X, Léveillé, Frédéric, Martel, Marc-Andre, Dakin, Kelly A, Hansen, Henrik H, Kaindl, Angela, Sifringer, Marco, Fowler, Jill, Stefovska, Vanya, Mckenzie, Grahame, Craigon, Marie, Corriveau, Roderick, Ghazal, Peter ORCID: https://orcid.org/0000-0003-0035-2228, Horsburgh, Karen, Yankner, Bruce A, Wyllie, David J A, Ikonomidou, Chrysanthy and Hardingham, Giles E 2008. Synaptic NMDA receptor activity boosts intrinsic antioxidant defenses. Nature Neuroscience 11 (4) , pp. 476-487. 10.1038/nn2071

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Publisher:	Nature Publishing Group
ISSN:	1097-6256
Date of Acceptance:	15 February 2008
Last Modified:	23 Oct 2022 14:18
URI:	https://orca.cardiff.ac.uk/id/eprint/113320

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