Cui Yongfei, Cao Kerun, Lin Huiyuan, Cui Sainan, Shen Chongkun, Wen Wenhao, Mo Haixin, Dong Zhaoyang, Bai Shasha, Yang Lei, Shi Yafei, Zhang Rong
School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China.
School of Fundamental Medical Science, Guangzhou University of Chinese Medicine, Guangzhou, China.
Front Pharmacol. 2020 Feb 26;11:102. doi: 10.3389/fphar.2020.00102. eCollection 2020.
More than 300 million people suffer from depressive disorders globally. People under early-life stress (ELS) are reportedly vulnerable to depression in their adulthood, and synaptic plasticity can be the molecular mechanism underlying such depression. Herein, we simulated ELS by using a maternal separation (MS) model and evaluated the behavior of Sprague-Dawley (SD) rats in adulthood through behavioral examination, including sucrose preference, forced swimming, and open-field tests. The behavior tests showed that SD rats in the MS group were more susceptible to depression- and anxiety-like behaviors than did the non-MS (NMS) group. Nissl staining analysis indicated a significant reduction in the number of neurons at the prefrontal cortex and hippocampus, including the CA1, CA2, CA3, and DG regions of SD rats in the MS group. Immunohistochemistry results showed that the percentages of synaptophysin-positive area in the prefrontal cortex and hippocampus (including the CA1, CA2, CA3, and DG regions) slice of the MS group significantly decreased compared with those of the NMS group. Western blot analysis was used to assess synaptic-plasticity protein markers, including postsynaptic density 95, synaptophysin, and growth-associated binding protein 43 protein expression in the cortex and hippocampus. Results showed that the expression levels of these three proteins in the MS group were significantly lower than those in the NMS group. LC-MS/MS analysis revealed no significant differences in the peak areas of sex hormones and their metabolites, including estradiol, testosterone, androstenedione, estrone, estriol, and 5β-dihydrotestosterone. Through the application of nontargeted metabolomics to the overall analysis of differential metabolites, pathway-enrichment results showed the importance of arginine and proline metabolism; pantothenate and CoA biosyntheses; glutathione metabolism; and the phenylalanine, tyrosine, and tryptophan biosynthesis pathways. In summary, the MS model caused adult SD rats to be susceptible to depression, which may regulate synaptic plasticity through arginine and proline metabolism; pantothenate and CoA biosyntheses; glutathione metabolism; and phenylalanine, tyrosine, and tryptophan biosyntheses.
全球有超过3亿人患有抑郁症。据报道，经历早期生活压力（ELS）的人成年后易患抑郁症，而突触可塑性可能是这种抑郁症的分子机制。在此，我们通过母体分离（MS）模型模拟ELS，并通过行为学检测，包括蔗糖偏好、强迫游泳和旷场试验，评估成年斯普拉格-道利（SD）大鼠的行为。行为测试表明，MS组的SD大鼠比非MS（NMS）组更容易出现抑郁和焦虑样行为。尼氏染色分析表明，MS组SD大鼠前额叶皮质和海马体（包括CA1、CA2、CA3和DG区）的神经元数量显著减少。免疫组织化学结果显示，与NMS组相比，MS组前额叶皮质和海马体（包括CA1、CA2、CA3和DG区）切片中突触素阳性区域的百分比显著降低。蛋白质免疫印迹分析用于评估突触可塑性蛋白标志物，包括突触后密度95、突触素和生长相关结合蛋白43在皮质和海马体中的蛋白表达。结果表明，MS组这三种蛋白的表达水平显著低于NMS组。液相色谱-串联质谱（LC-MS/MS）分析显示，性激素及其代谢产物（包括雌二醇、睾酮、雄烯二酮、雌酮、雌三醇和5β-二氢睾酮）的峰面积没有显著差异。通过非靶向代谢组学对差异代谢物进行整体分析，通路富集结果显示精氨酸和脯氨酸代谢、泛酸和辅酶A生物合成、谷胱甘肽代谢以及苯丙氨酸、酪氨酸和色氨酸生物合成途径的重要性。总之，MS模型使成年SD大鼠易患抑郁症，这可能通过精氨酸和脯氨酸代谢、泛酸和辅酶A生物合成、谷胱甘肽代谢以及苯丙氨酸、酪氨酸和色氨酸生物合成来调节突触可塑性。
