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Linking early-life NMDAR hypofunction and oxidative stress in schizophrenia pathogenesis

Abstract

Molecular, genetic and pathological evidence suggests that deficits in GABAergic parvalbumin-positive interneurons contribute to schizophrenia pathophysiology through alterations in the brain's excitation–inhibition balance that result in impaired behaviour and cognition. Although the factors that trigger these deficits are diverse, there is increasing evidence that they converge on a common pathological hub that involves NMDA receptor hypofunction and oxidative stress. These factors have been separately linked to schizophrenia pathogenesis, but evidence now suggests that they are mechanistically interdependent and contribute to a common schizophrenia-associated pathology.

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Figure 1: Human GRIN2 mutations associated with neurodevelopmental and psychiatric disorders.
Figure 2: Key functions of the glutathione antioxidant system.
Figure 3: Reciprocal links between NMDA receptor hypofunction and oxidative stress.
Figure 4: Synaptic activity boosts the capacity of neuronal antioxidant systems.
Figure 5: The astrocytic NFE2L2 pathway boosts the brain's antioxidant defences.

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Acknowledgements

The K.Q.D. laboratory is supported by the Swiss National Science Foundation (grants # 31–116689, # 310030_135736/1, #320030_122419), the National Center of Competence in Research (NCCR) SYNAPSY (The Synaptic Bases of Mental Diseases; grant # 51AU40_125759), the Avina Foundation, the Damm-Etienne Foundation and the Alamaya Foundation (to K.Q.D.). The G.E.H. laboratory is supported by the UK Medical Research Council, the Wellcome Trust, and a Biogen Idec/University of Edinburgh Joint Discovery Research Collaboration. The authors thank K. Marwick for preparing Figure 1. The authors also thank M. Cuenod, P. Steullet, K. Marwick and D. Wyllie for their helpful comments on the article.

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Correspondence to Giles E. Hardingham or Kim Q. Do.

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Hardingham, G., Do, K. Linking early-life NMDAR hypofunction and oxidative stress in schizophrenia pathogenesis. Nat Rev Neurosci 17, 125–134 (2016). https://doi.org/10.1038/nrn.2015.19

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