Menin Deficiency Leads to Depressive-like Behaviors in Mice by Modulating Astrocyte-Mediated Neuroinflammation
Menin Deficiency Leads to Depressive-like Behaviors in Mice by Modulating Astrocyte-Mediated Neuroinflammation
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Menin 缺乏通过调节星形胶质细胞介导的神经炎症导致小鼠出现抑郁样行为。
DOI：
10.1016/j.neuron.2018.08.031
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发表时间：
2018-11-07
期刊：
影响因子：
16.2
通讯作者：
Zhang, Jie
中科院分区：
文献类型：
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作者：
Leng, Lige;Zhuang, Kai;Zhang, Jie
星形胶质细胞功能障碍和炎症与抑郁症(MDD)的发病机制有关。然而，这些效应背后的机制在很大程度上仍不清楚。在这里，我们发现多发性内分泌肿瘤1型(MEN1；蛋白质：Menin)的表达在暴露于CUMS(慢性不可预测的温和应激)或脂多糖的小鼠的大脑中减弱。星形胶质细胞特异性MEN1减少(GcKO)导致小鼠抑郁样行为。在脑膜素缺乏的星形胶质细胞中，我们观察到核因子-kappa B的激活和IL-1β的产生增加，而GcKO小鼠的抑郁样行为可以通过核因子-kappa B抑制剂或IL-1β受体拮抗剂恢复。重要的是，我们在人类MEN1中发现了一个SNP，rs375804228，其中G503D替换与MDD发病的高风险相关。G503D替代消除了menin-p65的相互作用，从而增强了核因子-kappaB的激活和IL-1β的产生。我们的结果显示，脑膜素在调节抑郁症的神经炎症中具有明显的星形胶质细胞作用，表明脑膜素可能是MDD的一个有吸引力的治疗靶点。
Astrocyte dysfunction and inflammation are associated with the pathogenesis of major depressive disorder (MDD). However, the mechanisms underlying these effects remain largely unknown. Here, we found that multiple endocrine neoplasia type 1 (Men1; protein: menin) expression is attenuated in the brain of mice exposed to CUMS (chronic unpredictable mild stress) or lipopolysaccharide. Astrocyte-specific reduction of Men1 (GcKO) led to depressive-like behaviors in mice. We observed enhanced NF-kappa B activation and IL-1 beta production with menin deficiency in astrocytes, where depressive-like behaviors in GcKO mice were restored by NF-kappa B inhibitor or IL-1 beta receptor antagonist. Importantly, we identified a SNP, rs375804228, in human MEN1, where G503D substitution is associated with a higher risk of MDD onset. G503D substitution abolished menin-p65 interactions, thereby enhancing NF-kappa B activation and IL-1 beta production. Our results reveal a distinct astroglial role for menin in regulating neuroinflammation in depression, indicating that menin may be an attractive therapeutic target in MDD.