PMID- 23348010
OWN - NLM
STAT- MEDLINE
DCOM- 20131028
LR  - 20220309
IS  - 1873-2402 (Electronic)
IS  - 0006-3223 (Print)
IS  - 0006-3223 (Linking)
VI  - 73
IP  - 10
DP  - 2013 May 15
TI  - Social isolation exacerbates schizophrenia-like phenotypes via oxidative stress 
      in cortical interneurons.
PG  - 1024-34
LID - S0006-3223(12)01088-8 [pii]
LID - 10.1016/j.biopsych.2012.12.004 [doi]
AB  - 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 gamma-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 gamma coactivator-1alpha (PGC-1alpha), 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-1alpha downregulation in the NMDAR-deleted PV-positive interneurons, results 
      in oxidative stress, which, in turn, might contribute to exacerbation of 
      schizophrenia-like behavioral phenotypes.
CI  - Published by Elsevier Inc.
FAU - Jiang, Zhihong
AU  - Jiang Z
AD  - Unit on Genetics of Cognition and Behavior, National Institute of Mental Health, 
      National Institutes of Health, Department of Health and Human Services, Bethesda, 
      MD 20892-3710, USA.
FAU - Rompala, Gregory R
AU  - Rompala GR
FAU - Zhang, Shuqin
AU  - Zhang S
FAU - Cowell, Rita M
AU  - Cowell RM
FAU - Nakazawa, Kazu
AU  - Nakazawa K
LA  - eng
GR  - ZIA MH002895-03/Intramural NIH HHS/United States
GR  - ZIA MH002895-04/Intramural NIH HHS/United States
GR  - MH077955-05/MH/NIMH NIH HHS/United States
GR  - Z01 MH002895-01/Intramural NIH HHS/United States
GR  - K01 MH077955/MH/NIMH NIH HHS/United States
GR  - ZIA MH002895-05/Intramural NIH HHS/United States
GR  - ZIA MH002895-06/Intramural NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, N.I.H., Intramural
DEP - 20130121
PL  - United States
TA  - Biol Psychiatry
JT  - Biological psychiatry
JID - 0213264
RN  - 0 (Acetophenones)
RN  - 0 (Antioxidants)
RN  - 0 (Parvalbumins)
RN  - 0 (Proteins)
RN  - 0 (Reactive Oxygen Species)
RN  - 0 (Receptors, AMPA)
RN  - 0 (protein phosphatase inhibitor-2)
RN  - B6J7B9UDTR (acetovanillone)
RN  - EC 1.15.1.1 (Superoxide Dismutase)
RN  - P6W5IXV8V9 (glutamate receptor ionotropic, AMPA 2)
SB  - IM
MH  - Acetophenones/pharmacology/therapeutic use
MH  - Animals
MH  - Antioxidants/pharmacology/therapeutic use
MH  - Cerebral Cortex/drug effects/*pathology
MH  - Disease Models, Animal
MH  - Humans
MH  - Interneurons/drug effects/*physiology
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Transgenic
MH  - Oxidative Stress/drug effects/genetics/*physiology
MH  - Parvalbumins/metabolism
MH  - Phenotype
MH  - Proteins/genetics
MH  - Reactive Oxygen Species/metabolism
MH  - Receptors, AMPA/genetics
MH  - *Schizophrenia/drug therapy/etiology/pathology
MH  - *Schizophrenic Psychology
MH  - *Social Isolation
MH  - Superoxide Dismutase/metabolism
PMC - PMC3638045
MID - NIHMS430211
COIS- Conflict of Interest: The authors have no biomedical financial interests or 
      potential conflicts of interest to disclose.
EDAT- 2013/01/26 06:00
MHDA- 2013/10/29 06:00
PMCR- 2014/05/15
CRDT- 2013/01/26 06:00
PHST- 2012/05/21 00:00 [received]
PHST- 2012/12/07 00:00 [revised]
PHST- 2012/12/08 00:00 [accepted]
PHST- 2013/01/26 06:00 [entrez]
PHST- 2013/01/26 06:00 [pubmed]
PHST- 2013/10/29 06:00 [medline]
PHST- 2014/05/15 00:00 [pmc-release]
AID - S0006-3223(12)01088-8 [pii]
AID - 10.1016/j.biopsych.2012.12.004 [doi]
PST - ppublish
SO  - Biol Psychiatry. 2013 May 15;73(10):1024-34. doi: 10.1016/j.biopsych.2012.12.004. 
      Epub 2013 Jan 21.