Behrens and colleagues elegantly demonstrated that Nox2 contributes to oxidative stress and dysfunction of GABAergic interneurons after subchronic ketamine exposure in mice (13,44). Furthermore, Sorce and colleagues (45) suggested that Nox2 is a major source of ROS production in mPFC following acute ketamine exposure. Neuronal production of interleukin-6 (IL-6) appears to be necessary and sufficient for ketamine-mediated activation of NADPH oxidase in mouse brains (44). However, Nox2 seems not to play a major role in ROS production in our KO mice, because PWSI-induced exacerbation of oxidative stress was still robustly observed in mPFC and S1 cortex of the Nox2-deleted Ppp1r2-cre/fGluN1 KO animals (Figure S5A, B in Supplement 1). Our preliminary result using quantitative real-time RT-PCR also showed no detectable increase in IL-6 or Nox2 mRNA level in cortical tissues of KO mice compared to the fGluN1 controls (Figure S5F in Supplement 1), suggesting that NADPH oxidase Nox2 is not the main source of the elevated ROS in our animal model. We postulate that the impaired antioxidant capacity of PV interneurons is due to PGC-1α down-regulation enhanced ROS levels in response
