Social isolation exacerbates schizophrenia-like phenotypes via oxidative stress in cortical interneurons.

paper Cited Public

Authors: Jiang, Zhihong; Rompala, Gregory R; Zhang, Shuqin; Cowell, Rita M; Nakazawa, Kazu
Year: 2013
Journal: Biological psychiatry
PMID: 23348010
DOI: 10.1016/j.biopsych.2012.12.004
PMCID: PMC3638045

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.

Figure 1

Elevated cortical reactive oxygen species (ROS) production in Ppp1r2-cre/fGluN1 KO mice following post-weaning social isolation (PWSI). (A & B) PWSI exacerbated cortical ROS production in KO animals and chronic treatment with apocynin (+APO), an ROS scavenger, diminished cortical ROS production. Floxed-GluN1 (flox) or KO animals that underwent group-housing (group) or PWSI until 8 or 16 weeks old were injected with dihydroethidium (DHE) (4~5 animals per group). ROS levels in mPFC (A) and S1 cortex (B) were visualized by oxidized DHE (in red) in sections counterstained with DAPI (blue). For drug treatment, animals were subjected to apocynin treatment (+APO) from postnatal 2 weeks (4~5 animals per group) until injected with DHE at the age of 8 weeks or 16 weeks. (C & D) Relative ROS levels in mPFC (C) and S1 cortex (D) were quantified and normalized to the levels of 8 week-old group-housed fGluN1 controls. Without APO pretreatment, regardless of brain areas, PWSI ROS levels were elevated only in 8-week-old KO mice. PWSI also exacerbated the ROS elevation in the KO mice at 16 weeks old. Two-way ANOVA, F(1,12)=6.36, p= .027 for genotype x housing condition interaction at 8 week-old in mPFC. F(1,14)=14.01, p= .002 for genotype at 16 week-old in mPFC. F(1,12)=7.75, p= .017 for genotype x housing condition interaction at 8 week-old in S1 cortex. F(1,13)=5.39, p= .037 for genotype at 16 week-old in S1 cortex. Chronic APO treatment reversed the PWSI-induced ROS elevation at both ages in both brain regions. Post-hoc Fisher least significant difference test, *p < .05, #p< .01. Scale bar in (B): 50 μm.

Figure 2

Oxidative stress exacerbated schizophrenia-like behavioral phenotypes in KO mice. (A) Diagram of the ages of the animals used for apocynin treatment, social isolation and behavioral tests. (B) Chronic treatment with APO rescued the anxiety-like behavior of KO animals at 8 weeks of age following PWSI. Group-housed KO mice did not show anxiety-like behavioral; however, PWSI reduced a time spent in open arms by KO mice, but not by fGluN1 controls. F(1, 40) = 6.25, p= .0166. Post-hoc Fisher’s LSD test, flox vs KO, *p < .02 for PWSI). APO treatment increased KO’s stay time in open arms to the control level after PWSI (F(1, 51) = 6.20, p = .016 for genotype x drug treatment interaction, post-hoc Fisher LSD test, *p < .01.(C) Novelty-induced hyperlocomotion of KO animals was unaffected by APO. Repeated measures ANOVA showed significant genotype effect, F(10, 33) = 2.36, p = .031; but no drug effect, F(10, 33) = .70, p = .715, post-hoc Fisher’s LSD test, *p < .05, KO vs flox.(D) Chronic APO treatment rescued Y-maze spontaneous alternation deficits of KO mice at 12 weeks old. Before drug treatment, KO animals had significant reductions in alternation compared to flox controls regardless of housing conditions, and PWSI exacerbated the deficit (F(1,54) = 16.67, p = .00015 for genotype effect, F(1,54) = 8.47, p = .0052 for housing condition effect. This deficit in KO mice was reversed by APO treatment (F(1, 51)=4.49, p= .039 for drug effect, F(1, 51)=6.02, p= .018 for genotype effect. Post-hoc Fisher LSD, *p< .05, #p< .01.(E) Impaired PPI in KO animals at 12 weeks of age was partially rescued by APO treatment. Without APO treatment, KO mice showed PPI deficits, in particular at 72 and 74 dB prepulse intensities, irrespective of PWSI. Two-way repeated measure of ANOVA, F(4, 62)=4.88, p= .0017 for genotype effect, F(4.62)=0.32, p= .86 for genotype x housing condition interaction. Interestingly, PWSI impaired PPI of fGluN1 (flox) controls at 72 dB. APO treatment reversed the impairment of PPI at 74 dB~78 dB for PWSI KO mice, but not at 72 dB. PPI deficits at 72dB for PWSI flox controls were also alleviated by APO treatment. Post-hoc Fisher LSD test, *p< .05, #p< .01.(F) APO did not affect auditory startle reflex of the mice at the age of 12 weeks, regardless of genotype, housing condition, or drug treatment.(G) PWSI impaired hedonic-like/reward-seeking behavior of KO mice, but not fGluN1 controls, in saccharine preference test and APO treatment alleviated this deficit. Before drug treatment, F(1, 42)=4.30, p= .044 for genotype x housing condition interaction in the 0.03% saccharine solution test. After chronic treatment with APO, F(1, 43)=7.44, p= .0092 for drug effect in 0.03% saccharine solution test. Post-hoc Fisher LSD test, *p < .05, #p< .01 vs other groups.(H) Nest building deficits precipitated by PWSI were partially reversed by APO treatment. Before drug treatment, F(1, 198)=38.54, p< .00001 for genotype effect and F(1, 198)=9.35, p= .0025 for genotype x housing condition interaction. Post-hoc Fisher’s LSD test, *p< .05, compared with flox controls; ¶ p< .001, PWSI KO vs group-housed KO. APO partially alleviated nesting deficits at 12 or 16 week-old (F(1, 191)=47.25, p< .00001 for genotype effect, and F(1, 191)=5.31, p= .022 for APO effect. #p < .05, KO (+APO) vs KO (−APO); *p< .05, KO (+APO) vs flox (+APO)). Number of animals is indicated in parentheses or inside plot bars. ns, no significant difference; other abbreviations as in Figure 1.

Figure 3

Post-weaning social isolation (PWSI) increased DNA and lipid oxidative stress in KO mice, particularly in cortical PV interneurons. Brain sections containing S1 cortex from group-housed or PWSI-treated flox control and KO animals at 8 weeks old were double-stained with PV antibody (red) and DNA oxidative stress marker 8-OH-dG (green in A), or lipid peroxidation marker 4-HNE (green in B). Scale bar: 50 μm (A) and 200 μm (B).

Figure 4

Cortical PV expression in KO mice was down-regulated by post-weaning social isolation (PWSI) and was reversed by chronic treatment of apocynin (+APO). (A, B) Brain sections from group-housed or PWSI animals or PWSI animals under APO treatment (4~6 animals for each group, 8 week-old) were immunostained with parvalbumin (PV)antibody and visualized by Alexa488 (green fluorescence). (C) PV expression was significantly decreased in the mPFC and S1 cortex of KO animals after PWSI, but not in fGluN1 (flox) controls. However, PV IR reduction in KO animals can be alleviated by chronic treatment of apocynin. Post-hoc Tukey’s HSD test following two-way ANOVA, #p < .01, *p < .05. Scale bar: 100 μm. ns: no significant difference; other abbreviations as in Figure 1 and 3.

Figure 5

PGC-1α in KO mice was down-regulated by post-weaning social isolation (PWSI). (A, B) DIG-labeled PGC-1α mRNA antisense probe was used to detect PGC-1α mRNA (visualized by NBT-BCIP, blue precipitate) (A) or together with DNP-labeled PV mRNA antisense probe (visualized by AEC, red precipitate) to detect PGC-1α expression in PV-positive interneurons (B). Purple arrows in B-1 and B-2 indicate neurons with both PGC-1α and PV expression. Blue arrows indicate neurons with PGC-1α expression only. No red cells were detected, suggesting that PGC-1α is expressed in all the PV neurons.(C–E) Cortical expression of PGC-1α was significantly reduced in KO animals at 8 weeks old after PWSI. PGC-1α mRNA levels were examined by in situ hybridization using DIG-labeled PGC-1α mRNA antisense probe (C) and quantitative RT-PCR (5~6 animals for each group) with RNA from mPFC (D). Post-hoc Tukey’s HSD test following two-way ANOVA revealed no difference between group-housed GluN1 (flox) controls and KO animals, p = .958; however, PWSI exacerbated the reduction of PGC-1α mRNA in KO mice, but not in fGluN1 (flox) controls, *p < .02). PGC-1α protein levels in mPFC (5~8 animals for each group) were examined by Western blot (E). Post-hoc Tukey’s HSD test following two-way ANOVA revealed no difference between group-housed fGluN1 (flox) and KO animals at 8 week-old (p = .254); however, PWSI exacerbated the reduction of PGC-1α protein in KO mice, but not in fGluN1 (flox) controls, #p < .003. (F) A reduction in PGC-1α protein levels was observed in both group-housed and PWSI KO mice at the age of 16 weeks, F(1, 17)=34.90, p< .0001 for genotype effect, #p< .01, post-hoc Tukey’s HSD test. Chronic treatment with APO reversed the PGC-1α protein reduction in PWSI KO mice. Post-hoc Fisher LSD test, *p< .05. Scale bar: 200 μm. ns: no significant difference; other abbreviations as Figure 1.

Figure 6

Cortical ROS defense system was down-regulated by post-weaning social isolation (PWSI) in KO mice. (A) ROS-detoxifying enzymes GPX1, CAT1, SOD1, and SOD2 were down-regulated in the cortex of KO mice at 8 week-old after PWSI, as examined by quantitative RT-PCR using RNA from the medial prefrontal cortex (mPFC) (5~8 animals for each group). Post-hoc Fisher’s LSD test after two-way ANOVA indicated that expression of these enzymes in fGluN1 (flox) controls were not significant decreased after PWSI (p = .987 for GPX1, p =.750 for CAT1, p = .251 for SOD1, p = .146 for SOD2). However, the reduction was observed in KO mice. Post-hoc Fisher’s LSD test after two-way ANOVA, *p < .05, #p < .01. (B) PWSI exacerbated SOD activity (U/mg protein) in the mPFC of KO mice, not fGluN1 (flox) controls (animal number is indicated inside bars). Post-hoc Fisher’s LSD test after two-way ANOVA, *p < .05. ns: no significant difference; other abbreviations as Figure 1 and 5.

#	Section	Preview
0	Materials and Methods	All experimental procedures were carried out in accordance with guidelines published in the National…
1	Materials and Methods — Animals	Ppp1r2-cre/fGluN1 knockout mice or simply KO mice was generated as previously described (15).…
2	Materials and Methods — Post weaning social isolation (PWSI)	Both male and female mice were used for immuno-histological and biochemical studies, and only male…
3	Materials and Methods — In vivo detection of reactive oxygen species level	In vivo detection of reactive oxygen species (ROS) in mouse brains was performed as previously…
4	Materials and Methods — Chronic treatment with apocynin and behavioral analysis	From the age of 2 weeks, male KO mice and their littermate fGluN1 control mice received apocynin…
5	Materials and Methods — Non-radioisotopic double in situ hybridization	DNA fragments corresponding to murine PV cDNA (GenBank accession number: NM_013645) and PGC-1α cDNA…
6	Materials and Methods — Measurement of superoxide dismutase activity	Medial PFC tissue was dissected and homogenized in cold PBS (10% w/v) with a tissue sonicator. The…
7	Materials and Methods — Statistics	Differences between groups were assessed for normally distributed data using a Student’s t-test…
8	Results — Post-weaning social isolation (PWSI) augmented cortical ROS levels in KO mice	To investigate the involvement of oxidative stress in Ppp1r2-cre/fGluN1 KO mice, cortical ROS levels…
9	Results — Post-weaning social isolation (PWSI) augmented cortical ROS levels in KO mice	Next we tested whether apocynin (APO), an antioxidant and ROS scavenger, alleviated the elevation of…
10	Results — Oxidative stress exacerbated schizophrenia-like behavioral phenotypes	Behavioral tasks were conducted after chronic treatment with APO (Figure 2A) to investigate whether…
11	Results — Oxidative stress exacerbated schizophrenia-like behavioral phenotypes	Concordant with the emergence of oxidative stress by PWSI, the time spent in unprotected open arms…
12	Results — Oxidative stress exacerbated schizophrenia-like behavioral phenotypes	Spatial working memory deficits were evaluated using the spontaneous Y-maze alternation task, which…
13	Results — Oxidative stress exacerbated schizophrenia-like behavioral phenotypes	Prepulse inhibition (PPI) of the acoustic startle reflex is a measure of sensorimotor gating. In…
14	Results — Oxidative stress exacerbated schizophrenia-like behavioral phenotypes	The KO mice regardless of housing conditions showed novelty-induced hyperlocomotion at 8 weeks of…
15	Results — Oxidative stress exacerbated schizophrenia-like behavioral phenotypes	A two-bottle saccharine preference tested the hedonic-like/reward-seeking behavior. While KO mice at…
16	Results — Oxidative stress exacerbated schizophrenia-like behavioral phenotypes	Nest building behavior assessed social behavior. Without drug treatment, fGluN1 control mice…
17	Results — PWSI exacerbated oxidative stress in cortical PV interneurons in KO mice	The consequences of oxidative stress were examined by DNA oxidation and lipid peroxidation.…
18	Results — PWSI exacerbated oxidative stress in cortical PV interneurons in KO mice	To further evaluate the impact of oxidative stress on PV interneurons, we quantified parvalbumin-IR…
19	Results — PWSI downregulated cortical PGC-1α in KO mice	To investigate possible causes of increases in oxidative stress and concomitant PV-IR decrease in…

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Caught in vicious circles: a perspective on dynamic feed-forward loops driving oxidative stress in schizophrenia.	Cuenod M et al.	—	2022	→
Caught in vicious circles: a perspective on dynamic feed-forward loops driving oxidative stress in schizophrenia; Response to "Adaptive changes to oxidative stress in schizophrenia by Lena Palaniyappan".	Cuenod M et al.	—	2022	→
Clinical translational neuroimaging of the antioxidant effect of N-acetylcysteine on neural microstructure.	Yi SY et al.	—	2022	→
Dysregulation of prefrontal parvalbumin interneurons leads to adult aggression induced by social isolation stress during adolescence.	Li X et al.	—	2022	→
Factors Related to Passive Social Withdrawal and Active Social Avoidance in Schizophrenia.	Farina EA et al.	—	2022	→
Myelinating Co-Culture as a Model to Study Anti-NMDAR Neurotoxicity.	Sabet MF et al.	—	2022	→
Paliperidone alleviates MK-801-induced damage to prefrontal cortical neurons via the PP2A/PTEN pathway.	Wang J et al.	—	2022	→
Preclinical animal models of mental illnesses to translate findings from the bench to the bedside: Molecular brain mechanisms and peripheral biomarkers associated to early life stress or immune challenges.	Cattane N et al.	—	2022	→
PV-specific loss of the transcriptional coactivator PGC-1α slows down the evolution of epileptic activity in an acute ictogenic model.	Mackenzie-Gray Scott C et al.	—	2022	→
Altered dorsal functional connectivity after post-weaning social isolation and resocialization in mice.	Kim GS et al.	—	2021	→
Antiseizure effects of Anacyclus pyrethrum in socially isolated rats with and without a positive handling strategy.	Manouze H et al.	—	2021	→
Btbd11 is an inhibitory interneuron specific synaptic scaffolding protein that supports excitatory synapse structure and function	Bygrave AM et al.	—	2021	—
Clozapine attenuates mitochondrial dysfunction, inflammatory gene expression, and behavioral abnormalities in an animal model of schizophrenia.	Amiri S et al.	—	2021	→
Dysregulation of PGC-1α-Dependent Transcriptional Programs in Neurological and Developmental Disorders: Therapeutic Challenges and Opportunities.	McMeekin LJ et al.	—	2021	→
Early NMDA Receptor Ablation in Interneurons Causes an Activity-Dependent E/I Imbalance in vivo in Prefrontal Cortex Pyramidal Neurons of a Mouse Model Useful for the Study of Schizophrenia.	Pafundo DE et al.	—	2021	→
Estrogen-related Receptor Alpha (ERRα) is Required for PGC-1α-dependent Gene Expression in the Mouse Brain.	McMeekin LJ et al.	—	2021	→
Investigating potential associations between neurocognition/social cognition and oxidative stress in schizophrenia.	Cruz BF et al.	—	2021	→
Links Between Human and Animal Models of Trauma and Psychosis: A Narrative Review.	Tryon VL et al.	—	2021	→
Novel Biomarkers of Alzheimer's Disease: Based Upon N-methyl-D-aspartate Receptor Hypoactivation and Oxidative Stress.	Chiang TI et al.	—	2021	→
Nutritional Intervention with Dried Bonito Broth for the Amelioration of Aggressive Behaviors in Children with Prenatal Exposure to Dioxins in Vietnam: A Pilot Study.	Nishijo M et al.	—	2021	→
Overexpression of catalase in mitochondria mitigates changes in hippocampal cytokine expression following simulated microgravity and isolation.	Rubinstein L et al.	—	2021	→
[Oxidative stress in schizophrenia as a promising target for psychopharmacotherapy].	Potanin SS et al.	—	2021	→
Oxidative Stress-Related Mechanisms in Schizophrenia Pathogenesis and New Treatment Perspectives.	Ermakov EA et al.	—	2021	→
Prenatal MAM treatment altered fear conditioning following social isolation: Relevance to schizophrenia.	Bilecki W et al.	—	2021	→
Reduction of cortical parvalbumin-expressing GABAergic interneurons in a rodent hyperoxia model of preterm birth brain injury with deficits in social behavior and cognition.	Scheuer T et al.	—	2021	→
The dual hit hypothesis of schizophrenia: Evidence from animal models.	Guerrin CGJ et al.	—	2021	→
5-aminolevulinic acid inhibits oxidative stress and ameliorates autistic-like behaviors in prenatal valproic acid-exposed rats.	Matsuo K et al.	—	2020	→
A Role for PGC-1α in Transcription and Excitability of Neocortical and Hippocampal Excitatory Neurons.	McMeekin LJ et al.	—	2020	→
Astaxanthin Ameliorated Parvalbumin-Positive Neuron Deficits and Alzheimer's Disease-Related Pathological Progression in the Hippocampus of <i>App<sup>NL-G-F/NL-G-F</sup></i> Mice.	Hongo N et al.	—	2020	→
Early Adversity and Critical Periods: Neurodevelopmental Consequences of Violating the Expectable Environment.	Nelson CA et al.	—	2020	→
Interneuron NMDA Receptor Ablation Induces Hippocampus-Prefrontal Cortex Functional Hypoconnectivity after Adolescence in a Mouse Model of Schizophrenia.	Alvarez RJ et al.	—	2020	→
Previously incarcerated individuals with psychotic symptoms are more likely to report a history of solitary confinement.	Ryan AT et al.	—	2020	→
The origin of NMDA receptor hypofunction in schizophrenia.	Nakazawa K et al.	—	2020	→
The role of oxidative stress in cardiovascular disease caused by social isolation and loneliness.	Li H et al.	—	2020	→
Aging and Central Auditory Disinhibition: Is It a Reflection of Homeostatic Downregulation or Metabolic Vulnerability?	Ibrahim BA et al.	—	2019	→
Can N-Methyl-D-Aspartate Receptor Hypofunction in Schizophrenia Be Localized to an Individual Cell Type?	Bygrave AM et al.	—	2019	→
Hypofunctional Dopamine Uptake and Antipsychotic Treatment-Resistant Schizophrenia.	Amato D et al.	—	2019	→
Magnetic Resonance Spectroscopy in Schizophrenia: Evidence for Glutamatergic Dysfunction and Impaired Energy Metabolism.	Duarte JMN et al.	—	2019	→
Parvalbumin interneuron in the ventral hippocampus functions as a discriminator in social memory.	Deng X et al.	—	2019	→
Stress Exposure in Dopamine D4 Receptor Knockout Mice Induces Schizophrenia-Like Behaviors via Disruption of GABAergic Transmission.	Tan T et al.	—	2019	→
Clozapine attenuates mitochondrial burdens and abnormal behaviors elicited by phencyclidine in mice via inhibition of p47 <sup>phox</sup>; Possible involvements of phosphoinositide 3-kinase/Akt signaling.	Tran HQ et al.	—	2018	→
Gene-Environment Interaction in a Conditional NMDAR-Knockout Model of Schizophrenia.	Bygrave AM et al.	—	2018	→
Neurobiology and consequences of social isolation stress in animal model-A comprehensive review.	Mumtaz F et al.	—	2018	→
Non-motor Behavioral Alterations of PGC-1α-Deficient Mice - A Peculiar Phenotype With Slight Male Preponderance and No Apparent Progression.	Szalardy L et al.	—	2018	→
Sensorimotor gating deficits in "two-hit" models of schizophrenia risk factors.	Khan A et al.	—	2018	→
The use of antioxidant compounds in the treatment of first psychotic episode: Highlights from preclinical studies.	Schiavone S et al.	—	2018	→
Characterization of GABAergic marker expression in the chronic unpredictable stress model of depression.	Banasr M et al.	—	2017	→
DISC1 Modulates Neuronal Stress Responses by Gate-Keeping ER-Mitochondria Ca<sup>2+</sup> Transfer through the MAM.	Park SJ et al.	—	2017	→
Early enriched physical environment reverses impairments of the hippocampus, but not medial prefrontal cortex, of socially-isolated mice.	Cao M et al.	—	2017	→
Early Social Isolation Stress and Perinatal NMDA Receptor Antagonist Treatment Induce Changes in the Structure and Neurochemistry of Inhibitory Neurons of the Adult Amygdala and Prefrontal Cortex.	Castillo-Gómez E et al.	—	2017	→
European contribution to the study of ROS: A summary of the findings and prospects for the future from the COST action BM1203 (EU-ROS).	Egea J et al.	—	2017	→
Ingestion of dried-bonito broth (dashi) facilitates PV-parvalbumin-immunoreactive neurons in the brain, and affects emotional behaviors in mice.	Jargalsaikhan U et al.	—	2017	→
Microglia-derived neuregulin expression in psychiatric disorders.	Ikawa D et al.	—	2017	→
Oxidative stress-driven parvalbumin interneuron impairment as a common mechanism in models of schizophrenia.	Steullet P et al.	—	2017	→
Region-specific impairments in parvalbumin interneurons in social isolation-reared mice.	Ueno H et al.	—	2017	→
Repeated Neonatal Sevoflurane Exposure-Induced Developmental Delays of Parvalbumin Interneurons and Cognitive Impairments Are Reversed by Environmental Enrichment.	Ji MH et al.	—	2017	→
Social isolation stress and chronic glutathione deficiency have a common effect on the glutamine-to-glutamate ratio and myo-inositol concentration in the mouse frontal cortex.	Corcoba A et al.	—	2017	→
Spatial and temporal boundaries of NMDA receptor hypofunction leading to schizophrenia.	Nakazawa K et al.	—	2017	→
Anomalous bodily experiences and perceived social isolation in schizophrenia: An extension of the Social Deafferentation Hypothesis.	Michael J et al.	—	2016	→
Cortical PGC-1α-Dependent Transcripts Are Reduced in Postmortem Tissue From Patients With Schizophrenia.	McMeekin LJ et al.	—	2016	→
Early interventions in risk groups for schizophrenia: what are we waiting for?	Sommer IE et al.	—	2016	→
Environmental Enrichment Prevent the Juvenile Hypoxia-Induced Developmental Loss of Parvalbumin-Immunoreactive Cells in the Prefrontal Cortex and Neurobehavioral Alterations Through Inhibition of NADPH Oxidase-2-Derived Oxidative Stress.	Zhang M et al.	—	2016	→
Implications for reactive oxygen species in schizophrenia pathogenesis.	Koga M et al.	—	2016	→
Knockout of NMDA-receptors from parvalbumin interneurons sensitizes to schizophrenia-related deficits induced by MK-801.	Bygrave AM et al.	—	2016	→
Linking early-life NMDAR hypofunction and oxidative stress in schizophrenia pathogenesis.	Hardingham GE et al.	—	2016	→
Longitudinal assessment of neuronal 3D genomes in mouse prefrontal cortex.	Mitchell AC et al.	—	2016	→
Pharmacological targeting of redox regulation systems as new therapeutic approach for psychiatric disorders: A literature overview.	Schiavone S et al.	—	2016	→
Redox dysregulation, neuroinflammation, and NMDA receptor hypofunction: A "central hub" in schizophrenia pathophysiology?	Steullet P et al.	—	2016	→
Social Stress and Psychosis Risk: Common Neurochemical Substrates?	Mizrahi R	—	2016	→
The interneuron energy hypothesis: Implications for brain disease.	Kann O	—	2016	→
The involvement of N-methyl-D-aspartate receptor (NMDAR) subunit NR1 in the pathophysiology of schizophrenia.	Ju P et al.	—	2016	→
Alterations in the Nrf2-Keap1 signaling pathway and its downstream target genes in rat brain under stress.	Djordjevic J et al.	—	2015	→
Behaviour and prefrontal protein differences in C57BL/6N and 129 X1/SvJ mice.	Zhang X et al.	—	2015	→
Competition between the Brain and Testes under Selenium-Compromised Conditions: Insight into Sex Differences in Selenium Metabolism and Risk of Neurodevelopmental Disease.	Pitts MW et al.	—	2015	→
Mice with subtle reduction of NMDA NR1 receptor subunit expression have a selective decrease in mismatch negativity: Implications for schizophrenia prodromal population.	Featherstone RE et al.	—	2015	→
Oxidative stress as an etiological factor and a potential treatment target of psychiatric disorders. Part 2. Depression, anxiety, schizophrenia and autism.	Smaga I et al.	—	2015	→
Peroxisome proliferator-activated receptors α and γ are linked with alcohol consumption in mice and withdrawal and dependence in humans.	Blednov YA et al.	—	2015	→
Prolonged Period of Cortical Plasticity upon Redox Dysregulation in Fast-Spiking Interneurons.	Morishita H et al.	—	2015	→
Role of social factors on cell death, cerebral plasticity and recovery after stroke.	Venna VR et al.	—	2015	→
Sepsis-induced selective parvalbumin interneuron phenotype loss and cognitive impairments may be mediated by NADPH oxidase 2 activation in mice.	Ji MH et al.	—	2015	→
Brain state-dependent abnormal LFP activity in the auditory cortex of a schizophrenia mouse model.	Nakao K et al.	—	2014	→
Dysregulation of the axonal trafficking of nuclear-encoded mitochondrial mRNA alters neuronal mitochondrial activity and mouse behavior.	Kar AN et al.	—	2014	→
Highly energized inhibitory interneurons are a central element for information processing in cortical networks.	Kann O et al.	—	2014	→
Mice lacking selenoprotein P and selenocysteine lyase exhibit severe neurological dysfunction, neurodegeneration, and audiogenic seizures.	Byrns CN et al.	—	2014	→
Mice lacking the transcriptional coactivator PGC-1α exhibit alterations in inhibitory synaptic transmission in the motor cortex.	Dougherty SE et al.	—	2014	→
Oxidative/Nitrosative stress in psychiatric disorders: are we there yet?	O'Donnell P et al.	—	2014	→
PGC-1α provides a transcriptional framework for synchronous neurotransmitter release from parvalbumin-positive interneurons.	Lucas EK et al.	—	2014	→
Quercetin-3-O-glucuronide inhibits noradrenaline-promoted invasion of MDA-MB-231 human breast cancer cells by blocking β₂-adrenergic signaling.	Yamazaki S et al.	—	2014	→
Contribution of NMDA receptor hypofunction in prefrontal and cortical excitatory neurons to schizophrenia-like phenotypes.	Rompala GR et al.	—	2013	→
Convergence of genetic and environmental factors on parvalbumin-positive interneurons in schizophrenia.	Jiang Z et al.	—	2013	→
Oligodendrocyte plasticity with an intact cell body in vitro.	Makinodan M et al.	—	2013	→