The Microglial Innate Immune Receptor TREM2 Is Required for Synapse Elimination and Normal Brain Connectivity
The Microglial Innate Immune Receptor TREM2 Is Required for Synapse Elimination and Normal Brain Connectivity
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DOI：
10.1016/j.immuni.2018.04.016
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发表时间：
2018-05-15
期刊：
影响因子：
32.4
通讯作者：
Matteoli, Michela
中科院分区：
文献类型：
--
作者：
Filipello, Fabia;Morini, Raffaella;Matteoli, Michela
髓样细胞上表达的触发受体2（TREM 2）是一种小胶质细胞先天性免疫受体，与早期进行性痴呆、Nasu-Hakola病的致死形式相关，并与阿尔茨海默病的风险增加相关。在Trem 2失活突变的存在下，小胶质细胞吞噬毒性聚集体或凋亡膜的缺陷被认为是病理过程的起源。在这里，我们表明，TREM 2是必不可少的小胶质细胞介导的突触细化在大脑发育的早期阶段。Trem 2的缺乏导致突触消除受损，伴随着兴奋性神经传递增强和长程功能连接减少。Trem 2（-/-）小鼠表现出重复行为和改变的社交能力。TREM 2蛋白水平也与自闭症患者的症状严重程度呈负相关。这些数据揭示了TREM 2在神经回路塑造中的作用，并为受体参与神经发育疾病提供了证据。
The triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial innate immune receptor associated with a lethal form of early, progressive dementia, Nasu-Hakola disease, and with an increased risk of Alzheimer's disease. Microglial defects in phagocytosis of toxic aggregates or apoptotic membranes were proposed to be at the origin of the pathological processes in the presence of Trem2 inactivating mutations. Here, we show that TREM2 is essential for microglia-mediated synaptic refinement during the early stages of brain development. The absence of Trem2 resulted in impaired synapse elimination, accompanied by enhanced excitatory neurotransmission and reduced long-range functional connectivity. Trem2(-/-) mice displayed repetitive behavior and altered sociability. TREM2 protein levels were also negatively correlated with the severity of symptoms in humans affected by autism. These data unveil the role of TREM2 in neuronal circuit sculpting and provide the evidence for the receptor's involvement in neurodevelopmental diseases.