Involvement of reactive oxygen species (ROS) has been suggested in the development of psychiatric disorders. NOX1 is a non-phagocytic form of NADPH oxidase whose expression in the nervous system is negligible compared with other NOX isoforms. However, NOX1-derived ROS increase inflammatory pain and tolerance to opioid analgesia. To clarify the role of NOX1 in the brain, we examined depressive-like behaviors in mice deficient in Nox1 (Nox1-/Y). Depressive-like behaviors induced by chronic social defeat stress or administration of corticosterone (CORT) were significantly ameliorated in Nox1-/Y. Generation of ROS was significantly elevated in the prefrontal cortex (PFC) of mice administrated with CORT, while NOX1 mRNA was up-regulated only in the ventral tegmental area (VTA) among brain areas responsible for emotional behaviors. Delivery of miRNA against NOX1 to VTA restored CORT-induced depressive-like behaviors in wild-type littermates (WT). Administration of CORT to WT, but not to Nox1-/Y, significantly reduced transcript levels of brain-derived neurotrophic factor (BDNF), with a concomitant increase in DNA methylation of the promoter regions in bdnf. Delivery of miRNA against NOX1 to VTA restored the level of BDNF mRNA in WT PFC. Redox proteome analyses demonstrated that N-methyl-D-aspartate (NMDA) receptor 1 (NR1) was among the molecules redox-regulated by NOX1. In cultured cortical neurons, hydrogen peroxide significantly suppressed NMDA-induced up-regulation of BDNF transcripts in NR1-expressing cells, but not in cells harboring mutant NR1 (C744A). Together, these findings suggest a key role of NOX1 in depressive-like behaviors through NR1-mediated epigenetic modification of bdnf in the mesoprefrontal projection.
NADPH oxidase is a source of ROS that have been implicated in the pathogenesis of various neurological disorders. We presently showed the involvement of a non-phagocytic type of NADPH oxidase, NOX1, in major depressive disorders, including behavioral, biochemical, and anatomical changes in mice. The oxidation of NR1 by NOX1-derived ROS was demonstrated in PFC, which may be causally linked to the down-regulation of BDNF, promoting depressive-like behaviors. Given that NOX1 is up-regulated only in VTA but not in PFC, mesocortical projections appears to play a crucial role in NOX1-dependent depressive-like behaviors. Our study is the first to present the potential molecular mechanism underlying the development of major depression through the NOX1-induced oxidation of NR1 and epigenetic modification of bdnf.
Dr. Yabe-Nishimura reports having received research funding from Actelion Pharmaceuticals Japan Ltd. and Sanwa Kagaku Kenkyusho Co. Ltd. She is a cofounder of a startup company developing NOX inhibitors.
This work was supported by a Grant-in-Aid for Young Scientists (B) 22700397, Grant-in-Aid for Scientific research (C) 24500445, and Grant-in-Aid for Scientific research on Innovative Areas 25116521 from the Ministry of Education, Culture, Sports, Science and Technology of Japan (M.I.).