Department of Anatomy and Neurobiology, School of Basic Medical Science, Central South University, Changsha, Hunan Province 410013, China.
Clinical Anatomy & Reproductive Medicine Application Institute, School of Medicine, University of South China, Hengyang, Hunan Province 421001, China.
Brain Behav Immun. 2021 Jul;95:142-153. doi: 10.1016/j.bbi.2021.03.012. Epub 2021 Mar 15.
In recent years, our understanding of neural circuits associated with depression has increased. Although inherited factors are known to influence individual differences in the risk for this disorder, it has been difficult to identify specific genes that moderate circuit functions affecting depression. Genome-wide association studies have identified genetic variants of Cntn1 that are linked to major depressive disorders. Cntn1, a subset of the neural cell adhesion protein and immunoglobulin supergene family, participates in cell contact formation and axonal growth control and plays a role in degenerative and inflammatory disorders. However, neuronal substrates that mediate Cntn1 action on depression-like phenotypes and involved mechanisms are unclear. Here, we exploited chronic unpredictable stress (CUS) exposure and found that CUS treatment significantly increased hippocampal Cntn1 messenger RNA and protein expression in both mice and rats, but not in the medial prefrontal cortex, which presented a region-specific regulation. Using an adeno-associated virus-based approach to directly overexpress Cntn1 via stereotactic injection, we demonstrated that Cntn1 overexpression in the hippocampus triggered anxiety- and depression-like phenotypes in addition to microglia activation or phagocytosis in the hippocampus, resulting in upregulation of pro-inflammatory cytokine (IL1α, IL6, and Ccl2) mRNA expression and downregulation of anti-inflammatory cytokine (IL4 and CD206) mRNA expression, determined using real-time quantitative PCR, thus impairing hippocampal immature neurons in the dentate gyrus, determined using immunohistochemical staining for doublecortin, a specific marker for immature neurons. Collectively, our results identified Cntn1 as a novel risk gene involved in regulating anxiety and depression via functional actions in the hippocampus that is correlated with microglial activation or phagocytosis and reduced hippocampal immature neurons. These results may provide a better understanding of the pathophysiological mechanisms underlying the risk of depression-related disorders.
近年来，我们对与抑郁症相关的神经回路的理解有所增加。虽然已知遗传因素会影响个体患这种疾病的风险差异，但很难确定特定的基因来调节影响抑郁症的回路功能。全基因组关联研究已经确定了 Cntn1 的遗传变异与重度抑郁症有关。Cntn1 是神经细胞粘附蛋白和免疫球蛋白超基因家族的一个子集，参与细胞接触形成和轴突生长控制，在退行性和炎症性疾病中发挥作用。然而，介导 Cntn1 对抑郁样表型的作用的神经元基质及其涉及的机制尚不清楚。在这里，我们利用慢性不可预测的应激（CUS）暴露，并发现 CUS 处理在小鼠和大鼠的海马体中显著增加了Cntn1 信使 RNA 和蛋白质的表达，但在中前额叶皮层中没有增加，后者表现出特定区域的调节。使用基于腺相关病毒的方法通过立体定向注射直接过表达 Cntn1，我们证明了 Cntn1 在海马体中的过表达除了引发海马体中的小胶质细胞激活或吞噬作用外，还会引发焦虑和抑郁样表型，导致促炎细胞因子（IL1α、IL6 和 Ccl2）的 mRNA 表达上调和抗炎细胞因子（IL4 和 CD206）的 mRNA 表达下调，这是通过实时定量 PCR 确定的，从而损害了海马体齿状回中的未成熟神经元，这是通过双皮质蛋白（一种未成熟神经元的特异性标志物）的免疫组织化学染色确定的。总的来说，我们的研究结果确定 Cntn1 是一种新的风险基因，通过在海马体中的功能作用参与调节焦虑和抑郁，这与小胶质细胞的激活或吞噬作用以及减少海马体中的未成熟神经元有关。这些结果可能为更好地理解与抑郁症相关的疾病风险的病理生理机制提供了依据。
