MicroRNA-874/SIRT2信号通路调控海马神经发生参与抑郁症的作用机制研究

Depression is a common disorder with great suffering and high risk of suicide. Impaired hippocampal neurogenesis is a key factor for depression but its underlying mechanism remains unclear. Our previous findings demonstrated SIRT2 exerted anti-depression effect and promoted hippocampal neurogenesis, however, its upstream or downstream molecular events are far from being revealed. The persistent alteration of SIRT2 might be mediated by miRNAs and the downstream molecules to SIRT2 are suggested to be p53 or NF kappa B based on non-neuronal cell culture studies. In the piolet study on a small number of depressive patients, we found that miR-874 was overexpressed in the serum of depression patients. Besides, bioinformatics analysis showed that the 3’-UTR of SIRT2 had putative target sites for miR-874. Thus we hypothesize that miR-874 targets and regulates SIRT2 signaling pathway via p53/NF kappaB to influence of pathogenesis so as to be involved in depression. We will integrate neuropharmacology, molecular biology and animal behavior techniques using animal and cell models to investigate the contribution of this signaling pathway to neurogenesis and depression, as well. We hope to offer experiment evidenced and potential target for the future development of new antidepressant.

抑郁症是常见临床精神障碍，患者极为痛苦，自杀率高，海马神经元再生能力受损是抑郁症发病过程的重要因素，但其具体分子机制并不明确。我们前期发现SIRT2具有抗抑郁功能并促进海马神经发生，但其上下游调节通路不清。SIRT2可能被小分子RNA（miR）调控，产生持久改变；既往采用非神经元体系研究提示P53和NF-kB是SIRT2可能的下游信号分子。我们的小样本预实验显示miR-874在抑郁症患者血清中表达升高，SIRT2的3’-UTR富含miR-874结合位点。我们提出SIRT2- miR-874-p53/NF-kB通路调控神经新生，参与抑郁症的发病过程，并综合神经药理、分子生物和动物行为学方法在细胞和动物模型上验证该信号通路对神经新生和抑郁症表型的影响及其分子机制，期望为为开发有效的抗抑郁药物提供可能的靶点。

抑郁症是常见临床精神障碍，发病率随现代快节奏生活而急速攀升，而其治愈率低、自杀率高，对患者生活质量、家庭和谐、社会稳定都有严重不良影响。现有治疗手段效果不佳，探寻抑郁症的早期发病标志物和新的发病机制，将为抑郁症的诊断和治疗提供新策略。我们的研究结果显示，miR-874-5p在抑郁患者和模型大鼠血清中高表达，在大鼠海马脑区基因芯片分析结果中筛选出miR-874-5p下游两个基因sirt2和syt5，细胞学试验证明miR-874-5p对SIRT2和SYT5均有表达抑制作用；在抑郁模型小鼠海马中，通过腺相关病毒沉默miR-874-5p可显著缓解抑郁样行为；靶蛋白检测发现海马脑区SIRT2和SYT5在模型与对照组之间表达均无差异，而在PFC脑区SYT5明显减少；采用病毒定位注射手段在PFC脑区沉默miR-874-5p或过表达SYT5，均能显著改善抑郁样行为；形态学结果显示PFC区SYT5定位在兴奋性神经元突触前，在模型小鼠ACC过表达SYT5不仅恢复突触相关蛋白的表达，也部分上调了sEPSC的频率和幅度，改善小鼠抑郁样行为。最后通过抑郁症患者的血液样本进行miRNA和mRNA芯片分析，验证了miR-874-5p可作为抑郁诊断标志物，并找到多个其他可能的标志物，为后续的研究垫定了基础。本项目的研究结果阐明了miR-874-5p靶向SYT5调控前额叶皮层突触可塑性参与抑郁症的发生发展，证明miR-874-5p可以作为抑郁症的诊断分子，为抑郁症的发病机制和治疗新靶点提供了理论依据。