Microglia-Derived Vitamin D Binding Protein Mediates Synaptic Damage and Induces Depression by Binding to the Neuronal Receptor Megalin

IF 14.3 1区 材料科学 Q1 CHEMISTRY, MULTIDISCIPLINARY
Yan Kong, Xian Zhang, Ling Li, Te Zhao, Zihan Huang, Aini Zhang, Yun Sun, Jiao Jiao, Gaojia Zhang, Mengyu Liu, Yijun Han, Linfeng Yang, Zhijun Zhang
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Abstract

Vitamin D binding protein (VDBP) is a potential biomarker of major depressive disorder (MDD). This study demonstrates for the first time that VDBP is highly expressed in core emotion-related brain regions of mice susceptible to chronic unpredictable mild stress (CUMS). Specifically, the overexpression of microglia (MG)-derived VDBP in the prelimbic leads to depression-like behavior and aggravates CUMS-induced depressive phenotypes in mice, whereas conditional knockout of MG-derived VDBP can reverse both neuronal damage and depression-like behaviors. Mechanistically, the binding of MG-derived VDBP with the neuronal receptor megalin mediates the downstream SRC signaling pathway, leading to neuronal and synaptic damage and depression-like behaviors. These events may be caused by biased activation of inhibitory neurons and excitatory–inhibitory imbalance. Importantly, this study has effectively identified MG-derived VDBP as a pivotal mediator in the interplay between microglia and neurons via its interaction with the neuronal receptor megalin and intricate downstream impacts on neuronal functions, thus offering a promising therapeutic target for MDD.

Abstract Image

小胶质细胞来源的维生素D结合蛋白通过与神经元受体巨galin结合介导突触损伤和诱导抑郁。
维生素D结合蛋白(VDBP)是重度抑郁症(MDD)的潜在生物标志物。本研究首次表明,VDBP在易受慢性不可预测轻度应激(CUMS)影响的小鼠的核心情绪相关脑区高度表达。具体来说,小胶质细胞(MG)衍生的VDBP在大脑边缘前区过度表达会导致小鼠抑郁样行为,并加重cms诱导的抑郁表型,而有条件地敲除MG衍生的VDBP可以逆转神经元损伤和抑郁样行为。在机制上,mg源性VDBP与神经元受体meggalin结合介导下游SRC信号通路,导致神经元和突触损伤和抑郁样行为。这些事件可能是由抑制性神经元的偏激激活和兴奋-抑制失衡引起的。重要的是,本研究有效地确定了mg源性VDBP通过与神经元受体meggalin的相互作用以及对神经元功能的复杂下游影响,在小胶质细胞和神经元之间的相互作用中是一个关键的介质,从而为MDD提供了一个有希望的治疗靶点。
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来源期刊
Advanced Science
Advanced Science CHEMISTRY, MULTIDISCIPLINARYNANOSCIENCE &-NANOSCIENCE & NANOTECHNOLOGY
CiteScore
18.90
自引率
2.60%
发文量
1602
审稿时长
1.9 months
期刊介绍: Advanced Science is a prestigious open access journal that focuses on interdisciplinary research in materials science, physics, chemistry, medical and life sciences, and engineering. The journal aims to promote cutting-edge research by employing a rigorous and impartial review process. It is committed to presenting research articles with the highest quality production standards, ensuring maximum accessibility of top scientific findings. With its vibrant and innovative publication platform, Advanced Science seeks to revolutionize the dissemination and organization of scientific knowledge.
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