Center for Neuroscience, Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul, 02792, Republic of Korea.
Division of Bio-Medical Science and Technology, KIST School, Korea University of Science and Technology (UST), Seoul, 02792, Republic of Korea.
Sci Rep. 2020 Apr 24;10(1):6924. doi: 10.1038/s41598-020-63819-6.
Depression is a devastating mental disorder affected by multiple factors that can have genetic, environmental, or metabolic causes. Although previous studies have reported an association of dysregulated glucose metabolism with depression, its underlying mechanism remains elusive at the molecular level. A small percentage of glucose is converted into uridine diphosphate-N-acetylglucosamine (UDP-GlcNAc) via the hexosamine biosynthetic pathway, which serves as an immediate donor for protein O-GlcNAc modification. O-GlcNAcylation is a particularly common post-translational modification (PTM) in the brain, and the functional significance of O-GlcNAcylation in neurodegenerative diseases has been extensively reported. However, whether the degree of O-GlcNAc modification is associated with depressive disorder has not been examined. In this study, we show that increased O-GlcNAcylation levels reduce inhibitory synaptic transmission in the medial prefrontal cortex (mPFC), and that Oga mice with chronically elevated O-GlcNAcylation levels exhibit an antidepressant-like phenotype. Moreover, we found that virus-mediated expression of OGA in the mPFC restored both antidepressant-like behavior and inhibitory synaptic transmission. Therefore, our results suggest that O-GlcNAc modification in the mPFC plays a significant role in regulating antidepressant-like behavior, highlighting that the modulation of O-GlcNAcylation levels in the brain may serve as a novel therapeutic candidate for antidepressants.
抑郁症是一种由多种因素引起的破坏性精神障碍，这些因素可能有遗传、环境或代谢方面的原因。尽管之前的研究已经报告了葡萄糖代谢失调与抑郁症之间的关联，但在分子水平上，其潜在机制仍然难以捉摸。一小部分葡萄糖通过己糖胺生物合成途径转化为尿苷二磷酸-N-乙酰葡萄糖胺（UDP-GlcNAc），它作为蛋白质 O-GlcNAc 修饰的即时供体。O-GlcNAc 化是大脑中一种特别常见的翻译后修饰（PTM），O-GlcNAc 化在神经退行性疾病中的功能意义已经得到了广泛的报道。然而，O-GlcNAc 修饰的程度是否与抑郁症有关尚未被研究过。在这项研究中，我们表明，O-GlcNAc 化水平的升高会降低内侧前额叶皮层（mPFC）中的抑制性突触传递，而 Oga 小鼠中慢性升高的 O-GlcNAc 化水平表现出抗抑郁样表型。此外，我们发现，mPFC 中病毒介导的 OGA 表达恢复了抗抑郁样行为和抑制性突触传递。因此，我们的结果表明，mPFC 中的 O-GlcNAc 修饰在调节抗抑郁样行为中起着重要作用，这表明调节大脑中的 O-GlcNAc 化水平可能成为抗抑郁药物的一种新的治疗候选物。
