Oxidative stress-driven parvalbumin interneuron impairment as a common mechanism in models of schizophrenia.
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.
Centre for Psychiatric Neuroscience, Department of Psychiatry, Lausanne University Hospital, Prilly-Lausanne, Switzerland.
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P
Steullet
Centre for Psychiatric Neuroscience, Department of Psychiatry, Lausanne University Hospital, Prilly-Lausanne, Switzerland.
J-H
JH
Cabungcal
Laboratory for Psychiatric and Molecular Neuroscience, Harvard Medical School, McLean Hospital, Belmont, MA, USA.
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0000-0002-0702-1395
J
Coyle
Synaptic transmission H. Lundbeck A/S, Valby, Denmark.
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M
Didriksen
Departments of Neuroscience, Psychiatry and Psychology, University of Pittsburgh, Pittsburgh, PA, USA.
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K
Gill
Departments of Neuroscience, Psychiatry and Psychology, University of Pittsburgh, Pittsburgh, PA, USA.
A A
AA
Grace
Center for Brain Science, Department of Molecular Cellular Biology, Harvard University, Cambridge, MA USA.|FM Kirby Neurobiology Center, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
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TK
Hensch
George Washington Institute for Neuroscience, The George Washington University, Washington, DC, USA.
A-S
AS
LaMantia
F. Hoffmann-La Roche, Roche Pharmaceutical and Early Development, Neuroscience, Opthalmology &Rare Disease (NORD) DTA, Discovery Neuroscience, Roche Innovation Center Basel, Basel, Switzerland.
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L
Lindemann
George Washington Institute for Neuroscience, The George Washington University, Washington, DC, USA.
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TM
Maynard
Institute of Pharmacology and Toxicology, University of Zurich-Vetsuisse, Zurich, Switzerland.
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U
Meyer
Center for Brain Science, Department of Molecular Cellular Biology, Harvard University, Cambridge, MA USA.|FM Kirby Neurobiology Center, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.|Department of Psychiatry, Neuroscience, and Ophthalmology, Friedman Brain Institute, Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, NY, USA.
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0000-0002-1045-1337
H
Morishita
Neuroscience and Pain Research Unit, BioTherapeutics Research and Development, Pfizer, Cambridge, MA, USA.
P
P
O'Donnell
Laboratory for Psychiatric and Molecular Neuroscience, Harvard Medical School, McLean Hospital, Belmont, MA, USA.
M
M
Puhl
Centre for Psychiatric Neuroscience, Department of Psychiatry, Lausanne University Hospital, Prilly-Lausanne, Switzerland.
M
M
Cuenod
Centre for Psychiatric Neuroscience, Department of Psychiatry, Lausanne University Hospital, Prilly-Lausanne, Switzerland.
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Do
D000818:Animals; D000067877:Autism Spectrum Disorder / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D006179:Gyrus Cinguli / Q000378:metabolism; D006801:Humans; D007395:Interneurons / Q000378:metabolism / Q000502:physiology; D051379:Mice; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000235:genetics* / Q000502:physiology; D010320:Parvalbumins / Q000378:metabolism*; D012559:Schizophrenia / Q000235:genetics / Q000378:metabolism
D010320:Parvalbumins