Ibi Masakazu, Liu Junjie, Arakawa Noriaki, Kitaoka Shiho, Kawaji Ai, Matsuda Ken-Ichi, Iwata Kazumi, Matsumoto Misaki, Katsuyama Masato, Zhu Kai, Teramukai Satoshi, Furuyashiki Tomoyuki, Yabe-Nishimura Chihiro
Departments of Pharmacology.
Department of Medical Life Science, Graduate School of Medical Life Science, Yokohama City University, Yokohama 236-0004, Japan, and.
J Neurosci. 2017 Apr 12;37(15):4200-4212. doi: 10.1523/JNEUROSCI.2988-16.2017. Epub 2017 Mar 17.
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 in (). Depressive-like behaviors induced by chronic social defeat stress or administration of corticosterone (CORT) were significantly ameliorated in Generation 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 to , significantly reduced transcript levels of brain-derived neurotrophic factor (), with a concomitant increase in DNA methylation of the promoter regions in Delivery 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 of in the mesoprefrontal projection. NADPH 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 of .
活性氧（ROS）参与了精神疾病的发生发展。NOX1是烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶的一种非吞噬形式，与其他NOX亚型相比，其在神经系统中的表达可忽略不计。然而，NOX1衍生的ROS会增加炎性疼痛并降低对阿片类镇痛的耐受性。为了阐明NOX1在大脑中的作用，我们研究了缺乏（）的小鼠的抑郁样行为。慢性社会挫败应激或给予皮质酮（CORT）诱导的抑郁样行为在（）小鼠中得到显著改善。给予CORT的小鼠前额叶皮质（PFC）中ROS的生成显著升高，而在负责情绪行为的脑区中，NOX1 mRNA仅在腹侧被盖区（VTA）上调。将针对NOX1的微小RNA（miRNA）递送至VTA可恢复野生型（WT）同窝小鼠中CORT诱导的抑郁样行为。给予WT小鼠CORT可显著降低脑源性神经营养因子（）的转录水平，同时（）启动子区域的DNA甲基化增加，而给予（）小鼠CORT则无此现象。将针对NOX1的miRNA递送至VTA可恢复WT小鼠PFC中脑源性神经营养因子mRNA的水平。氧化还原蛋白质组分析表明，N-甲基-D-天冬氨酸受体1（NR1）是受NOX1氧化还原调节的分子之一。在培养的皮质神经元中，过氧化氢显著抑制了NR1表达细胞中N-甲基-D-天冬氨酸（NMDA）诱导的脑源性神经营养因子转录本上调，但对携带突变型NR1（C744A）的细胞无此作用。总之，这些发现表明NOX1在中前额叶投射中通过NR1介导的（）表观遗传修饰在抑郁样行为中起关键作用。NADPH氧化酶是活性氧（ROS）的来源，其与多种神经系统疾病的发病机制有关。我们目前的研究表明，一种非吞噬型的NADPH氧化酶NOX1参与了重度抑郁症，包括小鼠的行为、生化和解剖学变化。在小鼠前额叶皮质（PFC）中证实了NOX1衍生的ROS对NR1的氧化作用，这可能与脑源性神经营养因子的下调存在因果关系，从而促进抑郁样行为。鉴于NOX1仅在VTA中上调而不在PFC中上调，中皮质投射似乎在NOX1依赖性抑郁样行为中起关键作用。我们的研究首次揭示了通过NOX1诱导的NR1氧化和（）表观遗传修饰导致重度抑郁症发生的潜在分子机制。
