An interaction between genes and environment that impacts both early and late brain development may be necessary to trigger the onset of schizophrenia, which typically emerges in early adulthood (48). The present study demonstrated that PWSI-induced stress augmented cortical ROS levels in Ppp1r2-cre/GluN1 KO mice, and that ROS elevation is associated with the onset of schizophrenia-like symptoms. We further found that impaired antioxidant capacity due to PGC-1α down-regulation correlates with oxidative stress in PV interneurons in these KO mice. It is notable that no significant change in PGC-1α expression in the KO animals was observed until post-adolescent period (i.e., 8-week-old). Moreover, PWSI exacerbated the reduction of PGC-1α only in KO mice, which is consistent with a notion of gene x environment interaction. Interestingly, genetic association studies on chromosome 4p (49–51) implicated the PPARGC1A (gene for PGC-1α) locus in schizophrenia and bipolar disorder. Based on these findings, we postulate that PGC-1α is a possible candidate for the underlying mechanism of interplay between genetic predisposition and environmental insults in schizophrenia. In future experiments, it will be interesting to investigate whether overexpressing PGC-1α in Cre-targeted interneurons can alleviate oxidative stress and thereby rescue social isolation-exacerbated behavioral deficits.
