Hippocampal F3/Contactin plays a role in chronic stress-induced depressive-like effects and the antidepressant actions of vortioxetine in mice
Hippocampal F3/Contactin plays a role in chronic stress-induced depressive-like effects and the antidepressant actions of vortioxetine in mice
复制标题
海马 F3/Contactin 在小鼠慢性应激诱导的抑郁样作用和沃替西汀的抗抑郁作用中发挥作用
DOI：
10.1016/j.bcp.2022.115097
复制
发表时间：
2022-06-07
影响因子：
5.8
通讯作者：
Liu, Jian-Feng
中科院分区：
文献类型：
--
作者：
Chen, Yan-Mei;Fan, Hua;Liu, Jian-Feng
抑郁症是一种非常普遍的精神疾病，威胁着世界上近六分之一的人口。迄今为止，抑郁症的发病机制仍然难以捉摸，被认为取决于多种因素，其中慢性应激是关键。目前研究表明，抑郁症除了伴有单胺能神经元功能障碍外，还伴有海马神经发生障碍和脑源性神经营养因子（BDNF）-cAMP反应元件结合蛋白（CREB）信号级联反应降低等重要病理现象。F3/Contactin是一种细胞粘附分子，据报道与海马神经发生和BDNF-CREB信号传导相关。本研究假设F3/Contactin可能参与抑郁症的发生，并综合运用了免疫印迹、免疫荧光、病毒介导的基因转移和慢性应激抑郁症模型等多种方法。结果发现，慢性束缚应激（CRS）和慢性社交失败应激（CSDS）均显著降低海马F3/Contactin的表达。腺相关病毒（AAV）介导的海马F3/Contactin的过表达显著地阻止了CRS诱导的小鼠抑郁样行为和CSDS诱导的小鼠抑郁样行为。此外，海马F3/ Contactin过表达也完全逆转了CRS诱导和CSD诱导的小鼠海马BDNF-CREB信号传导和神经发生的功能障碍。此外，沃替西汀，一种多模式抗抑郁药，管理，完全改善CRS和CSDS对海马F3/ Contactin表达的抑制作用。与此相反，AAV介导的海马F3/Contactin的敲低显著消除了沃替西汀对CRS和CSDS的保护作用。总的来说，海马F3/Contactin与抑郁症有关，可能是一种新的抗抑郁药靶点。
Depression is a very prevalent psychiatric disorder which threats nearly one in six of the population in this world. To date, the pathogenesis of depression remains elusive and is thought to depend on multiple factors in which chronic stress is critical. Currently, it has been demonstrated that besides monoaminergic dysfunction, depression is accompanied by several other important pathological phenomena such as impaired neurogenesis and decreased brain-derived neurotrophic factor (BDNF)-cAMP response element binding protein (CREB) signaling cascade in the hippocampus. F3/Contactin is a cell-adhesion molecule which has been reported to correlate with hippocampal neurogenesis and BDNF-CREB signaling. Here we assumed that F3/Contactin may be implicated in depression, and various methods including western blotting, immunofluorescence, virus-mediated gene transfer and chronic stress models of depression were adopted together. It was found that both chronic restraint stress (CRS) and chronic social defeat stress (CSDS) significantly decreased the expression of F3/Contactin in the hippocampus. Adeno-associated virus (AAV)-mediated over-expression of hippocampal F3/Contactin notably prevented the CRS-induced and CSDS-induced depressive-like behaviors in mice. Moreover, hippocampal F3/ Contactin over-expression also fully reversed the CRS-induced and CSDS-induced dysfunction in the hippocampal BDNF-CREB signaling and neurogenesis of mice. Furthermore, administration of vortioxetine, a multimodalacting antidepressant, fully ameliorated the inhibitory actions of both CRS and CSDS on the hippocampal F3/ Contactin expression. In contrast, AAV-mediated knockdown of hippocampal F3/Contactin significantly abolished the protecting effects of vortioxetine against CRS and CSDS. Collectively, hippocampal F3/Contactin is implicated in depression and could be a novel antidepressant target.