31 March 2008. Oxidative damage occurs as part of normal aging and during the progression of many neurodegenerative diseases. How long a cell survives often depends on just how sturdy its defenses are against reactive oxygen species. Synaptic activity helps, according to a new study from Giles Hardingham and colleagues at the University of Edinburgh, Scotland. In a paper out March 23 online in Nature Neuroscience, the group presents data that synaptic activation of the NMDA-type glutamate receptor turns on several genes that boost antioxidant defenses.
The work could explain at least in part why synaptic activity protects neurons from death. The findings also suggest new targets for augmenting antioxidant activity to counteract the effects of aging or neurodegenerative diseases. “This is an important piece of work, elegantly detailing a previously unrecognized series of events emanating from normal NMDA-mediated synaptic activity that boost the antioxidant defenses of neurons,” writes Stuart Lipton of the Burnham Institute, La Jolla, California, in an accompanying News and Views piece.
Interested in whether antioxidant defenses in neurons are under regulation, first authors Sofia Papadia and Francesc Soriano first looked at the effect of NMDA glutamate receptor activity on oxidative stress. They found that the toxicity of the NMDAR blocker MK801 in perinatal rat cortex was accompanied by an increase in oxidative damage to cells, and an increase in sensitivity to hydrogen peroxide. Activating synaptic NMDARs, they found, protected the cells against oxidative damage and death induced by treatment with hydrogen peroxide. The protective effects stemmed from activating synaptic glutamate receptors, and not the extra synaptic receptors that are blamed for glutamate toxicity.
The antioxidant action of synaptic activity resulted from upregulation of the thioredoxin pathway. In that pathway, a family of Prx proteins contain a cysteine residue that neutralizes peroxides by forming cysteine sulfenic acid (-SOH), which is subsequently reduced by thioredoxin. In the face of overwhelming oxidative stress, the Prx proteins can become hyperoxidized to Prx–SO2H or Prx-SO3H, which are no longer substrates for thioredoxin. In neurons treated with hydrogen peroxide, the investigators found, Prx–SO2/3H proteins accumulated. Their levels were reduced by activation of NMDARs, suggesting that synaptic activity enhanced the thioredoxin system.
That enhancement was due to the coordinated expression of three thioredoxin pathway genes. First of all, synaptic activity suppressed expression of a thioredoxin inhibitor, Txnip. Interestingly, Txnip expression is elevated in brain from elderly people, suggesting that diminished activity of the thioredoxin system could play a role in age-related sensitivity to oxidative damage. Previous work has reported Txnip elevation in AD (see ARF related news story).
The other two genes, upregulated by synaptic activity, encode the reductases sestrin 2 and sulfiredoxin, which are capable of reducing hyperoxidized Prx–SO2/3H proteins, rendering them once again substrates for thioredoxin. Sestrin 2 and sulfiredoxin had not previously been seen in neurons, where Prx–SO2/3H adducts were considered dead ends of protein oxidation. “Heretofore, reversal of Prx-SO2/3H was not known to be enzymatically possible in mammalian neurons, and this reaction alone is a major finding, representing a potentially new therapeutic target,” Lipton writes in his commentary.
Further work established that synaptic activation repressed Txnip via the Akt pathway and phosphorylation of the FOXO transcription factor, while sestrin 2 and sulfiredoxin were induced via pathways involving the transcription factors C/EBPβ and AP-1, respectively.
To show that the thioredoxin system is important in mature neurons, the investigators looked at a brain ischemia model in adult mice. There, they found production of hyperoxidized Prx proteins, suggesting that the thioredoxin system is overwhelmed. Still, it is not clear how NMDAR activation might impact antioxidant pathways in the aging brain or in chronic disease.
The physiological relevance of these NMDA-stimulated antioxidant responses is not yet clear, though oxidative stress is clearly a major facet of neurodegenerative disease. For example, could increased synaptic activity, resulting in boosted antioxidant protection, help explain the observed effects of environmental enrichment, education, and a stimulating lifestyle on reducing the risk of AD? In their discussion, Hardingham and colleagues address that question when they write, “The possibility that environmental enrichment may, through altered or increased patterns of neuronal activity, result in increased antioxidant defenses in those brain regions that are more intensely used is intriguing.”
The activity-dependent functions of NMDAR in development are the focus of a second study out this week, this one led by Roger Nicoll of the University of California in San Francisco. First author Hillel Adesnik and colleagues report in PNAS online that eliminating NMDA receptors in cells before synaptogenesis results in not fewer synapses, as might be expected, but more. By selectively knocking out NDMA receptor expression in just a few neurons in hippocampal slice cultures, they were able to study the role of the receptor in development of synapses in an intact neuronal environment. “Our findings point to a crucial role for NMDA receptors in synaptic development, but demonstrate that their primary role is to limit, rather than promote, synapse maturation,” the authors write. The explanation for this, they find, is that NMDAR activation prevents AMPA receptors from entering developing synapses, similar to what happens in LTD in mature synapses. Functional maturation of developing synapses occurs only when strong or correlated activity results in recruitment of AMPAR receptors.—Pat McCaffrey.
Papadia S, Soriano FX, Léveillé 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. Synaptic NMDA receptor activity boosts intrinsic antioxidant defenses. Nat Neurosci. 2008 Mar 23; [Epub ahead of print] Abstract
Lipton SA. NMDA receptor activity regulates transcription of antioxidant pathways.
Nat Neurosci. 2008 Apr;11(4):381-382. Abstract
Adesnik H, Li G, During MJ, Pleasure SJ, Nicoll R. NMDA receptors inhibit synapse unsilencing during brain development. PNAS Early Edition. 2008 March 24. Abstract