Social Isolation Exacerbates Schizophrenia-Like Phenotypes via Oxidative Stress in Cortical Interneurons
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Background Our previous studies indicated that N-methyl-D-aspartate receptor (NMDAR) deletion from a subset of corticolimbic interneurons in the mouse brain during early postnatal development is sufficient to trigger several behavioral and pathophysiological features resembling the symptoms of human schizophrenia. Interestingly, many of these behavioral phenotypes are exacerbated by social isolation stress. However, the mechanisms underlying the exacerbating effects of social isolation are unclear.Methods With γ-aminobutyric acid-ergic interneuron-specific NMDAR hypofunction mouse model (Ppp1r2-Cre/fGluN1 knockout [KO] mice), we investigated whether oxidative stress is implicated in the social isolation-induced exacerbation of schizophrenia-like phenotypes and further explored the underlying mechanism of elevated oxidative stress in KO mice.Results The reactive oxygen species (ROS) level in the cortex of group-housed KO mice was normal at 8 weeks although increased at 16 weeks old. Postweaning social isolation (PWSI) augmented the ROS levels in KO mice at both ages, which was accompanied by the onset of behavioral phenotype. Chronic treatment with apocynin, an ROS scavenger, abolished markers of oxidative stress and partially alleviated schizophrenia-like behavioral phenotypes in KO mice. Markers of oxidative stress after PWSI were especially prominent in cortical parvalbumin (PV)-positive interneurons. The vulnerability of PV interneurons to oxidative stress was associated with downregulation of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), a master regulator of mitochondrial energy metabolism and antioxidation.Conclusions These results suggest that a PWSI-mediated impairment in antioxidant defense mechanisms, presumably mediated by PGC-1α downregulation in the NMDAR-deleted PV-positive interneurons, results in oxidative stress, which, in turn, might contribute to exacerbation of schizophrenia-like behavioral phenotypes.
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Severe psychosocial stress may be a more basic cause of the GABA interneuron changes in psychosis.
“A more basic cause may be severe psychosocial stress, which in preclinical studies has been found both to alter GAD67 expression in a variety of HPA axis-regulating regions, including the prefrontal cortex [89,90] , and increase oxidative stress in cortical parvalbumin-containing interneurons [91] .”
From The traumagenic neurodevelopmental model of psychosis revisited (2014) · cites this paper as [91]
The Abstract Results report that post-weaning social isolation increased oxidative-stress markers, especially in cortical parvalbumin-positive interneurons. The study tested mice with interneuron-specific NMDA receptor hypofunction, however, and the Discussion says isolation did not induce a robust oxidative-stress response in control mice. It therefore supports the cited preclinical finding, but not an unqualified claim that psychosocial stress causes these changes generally in psychosis. (LLM, conf=0.87)
Experimental — accuracy not yet measuredIn preclinical studies, severe psychosocial stress increases oxidative stress in cortical parvalbumin-containing interneurons.
“A more basic cause may be severe psychosocial stress, which in preclinical studies has been found both to alter GAD67 expression in a variety of HPA axis-regulating regions, including the prefrontal cortex [89,90] , and increase oxidative stress in cortical parvalbumin-containing interneurons [91] .”
From The traumagenic neurodevelopmental model of psychosis revisited (2014) · cites this paper as [91]
The Results and Discussion report that post-weaning social isolation increased oxidative-stress markers in cortical parvalbumin interneurons of NMDAR-deficient knockout mice. The claim omits that susceptibility was demonstrated in this specific mouse model, rather than established for cortical parvalbumin interneurons generally. (LLM, conf=0.87)
Experimental — accuracy not yet measuredRedox dysregulation has successfully been targeted to protect PVIs with antioxidants/redox regulators across several animal models.
“As convergent end point, redox dysregulation has successfully been targeted to protect PVIs with antioxidants/redox regulators across several animal models.”
From Oxidative stress-driven parvalbumin interneuron impairment as a common mechanism in models of schizophrenia (2017) · cites this paper as [83]
PVI function itself might be permanently impaired as a result of relatively mild transient NMDAR hypofunction in the developing mouse that does not induce neuronal death.
“Moreover, and as a result, PVI function itself might be permanently impaired as a result of relatively mild transient NMDAR hypofunction in the developing mouse that does not induce neuronal death 29,80 .”
From Linking early-life NMDAR hypofunction and oxidative stress in schizophrenia pathogenesis (2016) · cites this paper as [80]
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- Authors
- Jiang, Z., Rompala, G. R., Zhang, S., Cowell, R. M., & Nakazawa, K.
- Affiliations
- National Institutes of Health (US)
- University of Alabama at Birmingham (US)
- Corresponding author
- Nakazawa, Kazu
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2013-05
- Volume
- 73
- Issue
- 10
- Pages
- 1024-1034
- ISSN
- 0006-3223 (ISSN-L)
- PMC
- PMC3638045
- OpenAlex
- W1999810088
- Cited by
- 128
- References
- 56
- Citations by year
- 2026: 1 · 2025: 9 · 2024: 5 · 2023: 4 · 2022: 11 · 2021: 20 · 2020: 8 · 2019: 7 · 2018: 10 · 2017: 12 · 2016: 12 · 2015: 12 · 2014: 13 · 2013: 4
- FWCI
- 9.68
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Biological Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute of Mental Health (Z01MH002895, MH077955-05, ZIAMH002895, K01MH077955)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Keywords
- schizophrenia, social isolation, oxidative stress, reactive oxygen species, NMDA receptor, cortical interneurons, parvalbumin interneurons, PGC-1α, apocynin, antioxidant defense, mitochondrial bioenergetics
- MeSH terms
- Protein Phosphatase Inhibitory Proteins, Acetophenones, Animals, Antioxidants, Cerebral Cortex, Disease Models, Animal, Humans, Interneurons, Male, Mice, Inbred C57BL, Mice, Transgenic, Parvalbumins, Phenotype, Proteins, Schizophrenia, Schizophrenic Psychology, Social Isolation, Superoxide Dismutase, Reactive Oxygen Species, Receptors, AMPA, Oxidative Stress, Mice
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