Glial receptor PLXNB2 regulates schizophrenia-related stress perception via the amygdala.
Glial receptor PLXNB2 regulates schizophrenia-related stress perception via the amygdala.
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神经胶质受体PLXNB2通过杏仁核调节精神分裂症相关的压力感知
DOI：
10.3389/fimmu.2022.1005067
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发表时间：
2022
影响因子：
7.3
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中科院分区：
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压力是引发精神障碍的诱因。然而，精神分裂症患者的压力特征如何不同仍不清楚。压力还会诱发和加剧精神疾病中的免疫激活。神经丛蛋白(Plxn)及其配体信号素(Sema)是重要的细胞受体，在大脑和免疫系统中都具有多种功能。最近，Plxn/Sema在调节神经炎症中的作用也引起了人们的注意。在这里，当研究精神分裂症应激易感性的免疫机制时，我们发现Plxnb2在应激反应中的作用。对首发精神分裂症(FES)患者(FES-hs，n=51)和低应激(FES-l，n=50)患者和正常对照组(n=49)进行神经影像检查和全血总RNA测序。进一步探索了慢性不可预测应激(CUS)和杏仁核内PlxNB2功能阻断的小鼠模型，以描述靶基因的功能。与HCS相比，FES-hs患者的尾状核和丘脑较大(fdr分别为0.02和0.001)，而杏仁核较小(fdr=0.002)。血RNA-seq显示PLXNB2及其配体在患者组和HCS之间表达存在差异(FDR<；0.05~0.01)。FES-hs患者杏仁核大小和PLXNB2水平均与应激感觉呈负相关(β=0.9318，95%CI：0.058~1.886)。在小鼠中，Plxnb2在星形胶质细胞和小胶质细胞中丰富，而CUS减少其在星形胶质细胞中的表达(p<；0.05)。与生理盐水相比，其功能性阻断单抗抑制杏仁核Plxnb2引起小鼠焦虑(p<；0.05)、杏仁核增大(p<；0.05)和小胶质细胞分支(p<；0.001)。这些数据表明PLXNB2调节杏仁核依赖的应激反应。
Stress is a trigger for the development of psychiatric disorders. However, how stress trait differs in schizophrenia patients is still unclear. Stress also induces and exacerbates immune activation in psychiatric disorders. Plexins (Plxn) and its ligands semaphorins (Sema) are important cellular receptors with plural functions in both the brain and the immune system. Recently, the role of Plxn/Sema in regulation of neuroinflammation was also noticed. Here, when investigating immune mechanisms underlying stress susceptibility in schizophrenia, we discovered the role of Plxnb2 in stress response. Patients of first-episode schizophrenia (FES) with high stress (FES-hs, n=51) and low stress (FES-ls, n=50) perception and healthy controls (HCs) (n=49) were first recruited for neuroimaging and blood bulk RNA sequencing (RNA-seq). A mouse model of chronic unpredictable stress (CUS) and intra-amygdaloid functional blocking of Plxnb2 were further explored to depict target gene functions. Compared to HCs, FES-hs patients had bigger caudate and thalamus (FDR=0.02&0.001, respectively) whereas FES-ls patients had smaller amygdala (FDR=0.002). Blood RNA-seq showed differentially expressed PLXNB2 and its ligands among patient groups and HCs (FDR<0.05~0.01). Amygdaloid size and PLXNB2 level were both negatively correlated with stress perception (p<0.01&0.05, respectively), which fully mediated the amygdaloid positive association with PLXNB2 expression (β=0.9318, 95% CI: 0.058~1.886) in FES-hs patients. In mice, Plxnb2 was enriched in astrocytes and microglia and CUS reduced its expression in astrocytes (p<0.05). Inhibition of amygdaloid Plxnb2 by its functional blocking monoclonal antibody (mAb)-102 induced mice anxiety (p<0.05), amygdaloid enlargement (p<0.05), and microglial ramification (p<0.001) compared to saline. These data suggest that PLXNB2 regulates amygdala-dependent stress responses.