Oxidative stress-driven parvalbumin interneuron impairment as a common mechanism in models of schizophrenia

P. Steullet, J. H. Cabungcal, J. Coyle, M. Didriksen, K. Gill, A. A. Grace, T. K. Hensch, A. S. Lamantia, L. Lindemann, T. M. Maynard, U. Meyer, H. Morishita, P. O'Donnell, M. Puhl, M. Cuenod, K. Q. Do

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Parvalbumin inhibitory interneurons (PVIs) are crucial for maintaining proper excitatory/inhibitory balance and high-frequency neuronal synchronization. Their activity supports critical developmental trajectories, sensory and cognitive processing, and social behavior. Despite heterogeneity in the etiology across schizophrenia and autism spectrum disorder, PVI circuits are altered in these psychiatric disorders. Identifying mechanism(s) underlying PVI deficits is essential to establish treatments targeting in particular cognition. On the basis of published and new data, we propose oxidative stress as a common pathological mechanism leading to PVI impairment in schizophrenia and some forms of autism. A series of animal models carrying genetic and/or environmental risks relevant to diverse etiological aspects of these disorders show PVI deficits to be all accompanied by oxidative stress in the anterior cingulate cortex. Specifically, oxidative stress is negatively correlated with the integrity of PVIs and the extracellular perineuronal net enwrapping these interneurons. Oxidative stress may result from dysregulation of systems typically affected in schizophrenia, including glutamatergic, dopaminergic, immune and antioxidant signaling. As convergent end point, redox dysregulation has successfully been targeted to protect PVIs with antioxidants/redox regulators across several animal models. This opens up new perspectives for the use of antioxidant treatments to be applied to at-risk individuals, in close temporal proximity to environmental impacts known to induce oxidative stress.

Original languageEnglish
Pages (from-to)936-943
Number of pages8
JournalMolecular Psychiatry
Issue number7
StatePublished - 1 Jul 2017


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