Synaptic NMDA receptor activity boosts intrinsic antioxidant defenses
Open accessAbstract
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.
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Synaptic NMDAR activation boosts glutathione, thioredoxin, and peroxiredoxin systems via calcium-mediated signaling involving activation of CREB and inhibition of FOXO.
“Interestingly, synaptic NMDAR activation boosts GSH, thioredoxin, and peroxiredoxin systems via calcium-mediated signaling involving activation of CREB and inhibition of FOXO (Hardingham and Bading, 2010; Papadia et al., 2008).”
From Redox dysregulation, neuroinflammation, and NMDA receptor hypofunction: A “central hub” in schizophrenia pathophysiology? (2016) · cites this paper as Papadia et al., 2008
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- Authors
- Papadia, S., Soriano, F. X., Léveillé, F., Martel, M.-A., Dakin, K. A., Hansen, H. H., Kaindl, A., Sifringer, M., Fowler, J., Stefovska, V., Mckenzie, G., Craigon, M., Corriveau, R., Ghazal, P., Horsburgh, K., Yankner, B. A., Wyllie, D. J. A., Ikonomidou, C., & Hardingham, G. E.
- Affiliations
- University of Edinburgh (GB)
- Harvard University (US)
- Technische Universität Dresden (DE)
- Inserm (FR)
- MRC Cancer Unit (GB)
- Coriell Institute For Medical Research (US)
- Corresponding author
- Hardingham, Giles E
- ORCID
- Venue
- Nature Neuroscience
- Published
- 2008-03-23
- Volume
- 11
- Issue
- 4
- Pages
- 476-487
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC2556874
- OpenAlex
- W2006569015
- Cited by
- 498
- References
- 54
- Citations by year
- 2026: 3 · 2025: 12 · 2024: 7 · 2023: 14 · 2022: 18 · 2021: 28 · 2020: 22 · 2019: 20 · 2018: 35 · 2017: 32 · 2016: 30 · 2015: 24 · 2014: 35 · 2013: 37 · 2012: 53
- FWCI
- 17.40
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (submittedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
- Funders
- Wellcome Trust (078178)
- Medical Research Scotland
- Tenovus
- National Institutes of Health
- Biotechnology and Biological Sciences Research Council (BB/D011388/1)
- National Institute on Aging (P30-AG 10161, P30AG010161)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Keywords
- NMDA receptor, synaptic activity, antioxidant defense, thioredoxin, peroxiredoxin, TXNIP, oxidative stress, Sestrin2, sulfiredoxin, C/EBPβ, AP-1, forkhead box O, transcriptional regulation, extrasynaptic NMDA receptors
- MeSH terms
- Sestrins, Animals, Antioxidants, Carrier Proteins, Cells, Cultured, Cerebral Cortex, Gene Expression Regulation, Synaptic Transmission, Neurons, Nuclear Proteins, Peroxidases, Proteins, Synapses, Thioredoxins, Transcription, Genetic, Signal Transduction, Receptors, N-Methyl-D-Aspartate, Oxidative Stress, Oxidoreductases Acting on Sulfur Group Donors, Mice, Rats, Peroxiredoxins
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