Du Yuru, Shi Yun, Wang Xi, Song Han, Wang Xinhao, Hao Ying, Zhao Ye, Guo Xiangfei, Shi Mengxu, Gong Miao, Song Li, Wang Sheng, Gao Yuan, Shi Haishui
Hebei Key Laboratory of Neurophysiology, Shijiazhuang, China.
Neuroscience Research Center, Institute of Medical and Health Science, Hebei Medical University, Shijiazhuang, China.
J Neurochem. 2022 Oct;163(2):133-148. doi: 10.1111/jnc.15680. Epub 2022 Aug 4.
Depression is a global health problem, and there is a pressing need for a better understanding of its pathogenesis. Semaphorin 3B (Sema 3B) is an important axon guidance molecule that is primarily expressed in neurons and contributes to synaptic plasticity. Our previous studies using a high-throughput microarray assay suggested that Sema 3B expression was tremendously decreased during the development of depression, but the specific role and mechanisms of Sema 3B in depression are still unknown. Herein, we report that levels of Sema 3B protein are decreased in the hippocampus and serum of chronic mild stress (CMS)-treated mice. Increasing the levels of Sema 3B, either by injecting AAV-Sema 3B into the hippocampus or by injecting recombinant Sema 3B protein into the lateral ventricles, alleviated CMS-induced depression-like behaviours and enhanced the resistance to acute stress by increasing dendritic spine density in hippocampal neurons. In contrast, interfering with the function of Sema 3B by injecting anti-Sema 3B antibody into the lateral ventricles decreased the resistance to acute stress. In vitro, corticosterone (CORT) treatment decreased the survival rate and protein levels of Sema 3B and synapse-associated proteins in HT22 cells. Overexpression of Sema 3B improved the decreased survival rate caused by CORT by inhibiting apoptosis and increasing levels of synaptic-associated proteins, and knockdown of Sema 3B reduces the cellular resistance to CORT and the levels of synapse-associated proteins. These findings represent the first evidence for the neuroprotective mechanism of Sema 3B against stresses, suggesting that Sema 3B could be a promising novel target for the prevention and treatment of depression.
抑郁症是一个全球性的健康问题，迫切需要更好地了解其发病机制。信号素3B（Sema 3B）是一种重要的轴突导向分子，主要在神经元中表达，并有助于突触可塑性。我们之前使用高通量微阵列分析的研究表明，在抑郁症发展过程中，Sema 3B的表达显著降低，但Sema 3B在抑郁症中的具体作用和机制仍不清楚。在此，我们报告，在慢性轻度应激（CMS）处理的小鼠海马和血清中，Sema 3B蛋白水平降低。通过向海马注射腺相关病毒-Sema 3B或向侧脑室注射重组Sema 3B蛋白来提高Sema 3B水平，可减轻CMS诱导的抑郁样行为，并通过增加海马神经元的树突棘密度来增强对急性应激的抵抗力。相反，通过向侧脑室注射抗Sema 3B抗体来干扰Sema 3B的功能，会降低对急性应激的抵抗力。在体外，皮质酮（CORT）处理降低了HT22细胞中Sema 3B和突触相关蛋白的存活率和蛋白水平。Sema 3B的过表达通过抑制细胞凋亡和增加突触相关蛋白水平改善了由CORT引起的存活率降低，而Sema 3B的敲低则降低了细胞对CORT的抵抗力和突触相关蛋白的水平。这些发现首次证明了Sema 3B对抗应激的神经保护机制，表明Sema 3B可能是预防和治疗抑郁症的一个有前景的新靶点。
