Synaptic NMDA receptor activity boosts intrinsic antioxidant defenses

S. Papadia; F. X. Soriano; F. Leveille; M. A. Martel; K. A. Dakin; H. H. Hansen; A. Kaindl; M. Sifringer; J. Fowler; V. Stefovska; G. McKenzie; Marie Craigon; R. Corriveau; P. Ghazal; K. Horsburgh; B. A. Yankner; D. J. Wyllie; C. Ikonomidou; G. E. Hardingham

doi:10.1038/nn2071

Synaptic NMDA receptor activity boosts intrinsic antioxidant defenses

S. Papadia, F. X. Soriano, F. Leveille, M. A. Martel, K. A. Dakin, H. H. Hansen, A. Kaindl, M. Sifringer, J. Fowler, V. Stefovska, G. McKenzie, Marie Craigon, R. Corriveau, P. Ghazal, K. Horsburgh, B. A. Yankner, D. J. Wyllie, C. Ikonomidou, G. E. Hardingham

Research output: Contribution to journal › Article › peer-review

Abstract / Description of output

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.

Original language	English
Pages (from-to)	476-487
Number of pages	12
Journal	Nature Neuroscience
Volume	11
Issue number	4
DOIs	https://doi.org/10.1038/nn2071
Publication status	Published - Apr 2008

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10.1038/nn2071

Synaptic NMDA receptor activity boosts intrinsic antioxidant defenses
Published in final edited form as: Nat Neurosci. 2008 April ; 11(4): 476–487. doi:10.1038/nn2071.
Accepted author manuscript, 6.8 MB

http://www.nature.com/neuro/journal/v11/n4/abs/nn2071.html

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Papadia, S., Soriano, F. X., Leveille, 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., Ikonomidou, C., & Hardingham, G. E. (2008). Synaptic NMDA receptor activity boosts intrinsic antioxidant defenses. Nature Neuroscience, 11(4), 476-487. https://doi.org/10.1038/nn2071

@article{438cb23a29eb46db94b8d2681f616a64,

title = "Synaptic NMDA receptor activity boosts intrinsic antioxidant defenses",

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.",

author = "S. Papadia and Soriano, {F. X.} and F. Leveille and Martel, {M. A.} and Dakin, {K. A.} and Hansen, {H. H.} and A. Kaindl and M. Sifringer and J. Fowler and V. Stefovska and G. McKenzie and Marie Craigon and R. Corriveau and P. Ghazal and K. Horsburgh and Yankner, {B. A.} and Wyllie, {D. J.} and C. Ikonomidou and Hardingham, {G. E.}",

year = "2008",

month = apr,

doi = "10.1038/nn2071",

language = "English",

volume = "11",

pages = "476--487",

journal = "Nature Neuroscience",

issn = "1097-6256",

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Papadia, S, Soriano, FX, Leveille, F, Martel, MA, Dakin, KA, Hansen, HH, Kaindl, A, Sifringer, M, Fowler, J, Stefovska, V, McKenzie, G, Craigon, M, Corriveau, R, Ghazal, P, Horsburgh, K, Yankner, BA, Wyllie, DJ, Ikonomidou, C & Hardingham, GE 2008, 'Synaptic NMDA receptor activity boosts intrinsic antioxidant defenses', Nature Neuroscience, vol. 11, no. 4, pp. 476-487. https://doi.org/10.1038/nn2071

TY - JOUR

T1 - Synaptic NMDA receptor activity boosts intrinsic antioxidant defenses

AU - Papadia, S.

AU - Soriano, F. X.

AU - Leveille, F.

AU - Martel, M. A.

AU - Dakin, K. A.

AU - Hansen, H. H.

AU - Kaindl, A.

AU - Sifringer, M.

AU - Fowler, J.

AU - Stefovska, V.

AU - McKenzie, G.

AU - Craigon, Marie

AU - Corriveau, R.

AU - Ghazal, P.

AU - Horsburgh, K.

AU - Yankner, B. A.

AU - Wyllie, D. J.

AU - Ikonomidou, C.

AU - Hardingham, G. E.

PY - 2008/4

Y1 - 2008/4

N2 - 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.

AB - 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.

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U2 - 10.1038/nn2071

DO - 10.1038/nn2071

M3 - Article

SN - 1097-6256

VL - 11

SP - 476

EP - 487

JO - Nature Neuroscience

JF - Nature Neuroscience

IS - 4

ER -

Synaptic NMDA receptor activity boosts intrinsic antioxidant defenses

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n/a: The control of transcriptional corepressors by synaptic activity

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Synaptic NMDA receptor activity boosts intrinsic antioxidant defenses

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n/a: The control of transcriptional corepressors by synaptic activity

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