Depressive-Like Behaviors Are Regulated by NOX1/NADPH Oxidase by Redox Modification of NMDA Receptor 1.
Involvement of reactive oxygen species (ROS) has been suggested in the development of psychiatric disorders. NOX1 is a nonphagocytic 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 inNox1(Nox1-/Y). Depressive-like behaviors induced by chronic social defeat stress or administration of corticosterone (CORT) were significantly ameliorated inNox1-/YGeneration of ROS was significantly elevated in the prefrontal cortex (PFC) of mice administrated with CORT, while NOX1 mRNA was upregulated 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 (WT) littermates. Administration of CORT to WT, but not toNox1-/Y, significantly reduced transcript levels of brain-derived neurotrophic factor (bdnf), with a concomitant increase in DNA methylation of the promoter regions inbdnfDelivery of miRNA against NOX1 to VTA restored the level of BDNF mRNA in WT PFC. Redox proteome analyses demonstrated that NMDA receptor 1 (NR1) was among the molecules redox regulated by NOX1. In cultured cortical neurons, hydrogen peroxide significantly suppressed NMDA-induced upregulation 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 ofbdnfin the mesoprefrontal projection.SIGNIFICANCE STATEMENTNADPH oxidase is a source of reactive oxygen species (ROS) that have been implicated in the pathogenesis of various neurological disorders. We presently showed the involvement of a nonphagocytic 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 prefrontal cortex (PFC), which may be causally linked to the downregulation of BDNF, promoting depressive-like behaviors. Given that NOX1 is upregulated only in VTA but not in PFC, mesocortical projections appear 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 ofbdnf.
Departments of Pharmacology.
Masakazu
0000-0003-1414-100X
M
Ibi
Departments of Pharmacology.
Junjie
J
Liu
Department of Medical Life Science, Graduate School of Medical Life Science, Yokohama City University, Yokohama 236-0004, Japan, and.
Noriaki
N
Arakawa
Division of Pharmacology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
Shiho
S
Kitaoka
Departments of Pharmacology.
Ai
A
Kawaji
Anatomy and Neurobiology, and.
Ken-Ichi
KI
Matsuda
Departments of Pharmacology.
Kazumi
K
Iwata
Departments of Pharmacology.
Misaki
M
Matsumoto
Radioisotope Center, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
Masato
0000-0001-8938-1740
M
Katsuyama
Departments of Pharmacology.
Kai
K
Zhu
Biostatistics, and.
Satoshi
S
Teramukai
Division of Pharmacology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
Tomoyuki
T
Furuyashiki
Departments of Pharmacology, nchihiro@koto.kpu-m.ac.jp.
Chihiro
C
Yabe-Nishimura
D000818:Animals; D003866:Depressive Disorder / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009247:NADH, NADPH Oxidoreductases / Q000172:deficiency* / Q000235:genetics; D000074624:NADPH Oxidase 1; D019255:NADPH Oxidases / Q000172:deficiency; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction; D017397:Prefrontal Cortex; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*
C121673:Gprin1 protein, mouse; D009419:Nerve Tissue Proteins; D016194:Receptors, N-Methyl-D-Aspartate; D009247:NADH, NADPH Oxidoreductases; D000074624:NADPH Oxidase 1; D019255:NADPH Oxidases; C000614711:NOX1 protein, mouse
BDNF; NADPH oxidase; NMDA receptor; depressive-like behavior; mesoprefrontal projection; redox