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.
Key Words
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Article info
Publication history
Published online: January 23, 2013
Accepted:
December 8,
2012
Received in revised form:
December 7,
2012
Received:
May 21,
2012
Identification
Copyright
Published by Elsevier Inc.
