Abstract：
Synaptic abnormality is an important pathologic feature of autism spectrum disorders (ASDs) and responsible for various behavioral defects in these neurodevelopmental disorders. Microglia are the major immune cells in the brain and also play an important role in synapse refinement. Although dysregulated synaptic pruning by microglia during the brain development has been associated with ASDs, the underlying mechanism has yet to be fully elucidated. Herein, we observed that expression of Transmembrane protein 59 (TMEM59), a protein recently shown to regulate microglial function, was decreased in autistic patients. Furthermore, we found that both male and female mice with either complete or microglia-specific loss of Tmem59 developed ASD-like behaviors. Microglial TMEM59-deficient mice also exhibited enhanced excitatory synaptic transmission, increased dendritic spine density, and elevated levels of excitatory synaptic proteins in synaptosomes. TMEM59-deficient microglia had impaired capacity for synapse engulfment both in vivo and in vitro. Moreover, we demonstrated that TMEM59 interacted with the C1q receptor CD93 and TMEM59 deficiency promoted CD93 protein degradation in microglia. Downregulation of CD93 in microglia also impaired synapse engulfment. These findings identify a crucial role of TMEM59 in modulating microglial function on synapse refinement during brain development and suggest that TMEM59 deficiency may contribute to ASDs through disrupting phagocytosis of excitatory synapse and thus distorting the excitatory-inhibitory (E/I) neuronal activity balance.SIGNIFICANCE STATEMENT Microglia play an important role in synapse refinement. Dysregulated synaptic pruning by microglia during brain development has been associated with autism spectrum disorders (ASDs). However, the underlying mechanism has yet to be fully elucidated. Herein, we observe that the expression of Transmembrane protein 59 (TMEM59), an autophagy-related protein, is decreased in autistic patients. Moreover, we find ASD-like behaviors in mice with complete loss and with microglia-specific loss of Tmem59 Mechanistic studies reveal that TMEM59 deficiency in microglia impairs their synapse engulfment ability likely through destabilizing the C1q receptor CD93, thereby leading to enhanced excitatory neurotransmission and increased dendritic spine density. Our findings demonstrate a crucial role of microglial TMEM59 in early neuronal development and provide new insight into the etiology of ASDs.
摘要：
突触异常是自闭症谱系障碍（ASD）的重要病理特征，是这些神经发育障碍中各种行为缺陷的原因。小胶质细胞是大脑中主要的免疫细胞，在突触细化中也起着重要作用。尽管在大脑发育过程中小胶质细胞的突触修剪失调与ASD有关，潜在的机制尚未完全阐明。在这里，我们观察到跨膜蛋白59（TMEM59）的表达，最近显示出一种调节小胶质细胞功能的蛋白质，在自闭症患者中有所下降。此外，我们发现Tmem59完全缺失或小胶质细胞特异性缺失的雄性和雌性小鼠均出现ASD样行为.小胶质细胞TMEM59缺陷小鼠也表现出增强的兴奋性突触传递，树突状脊柱密度增加，和突触体中兴奋性突触蛋白水平升高。TMEM59缺陷的小胶质细胞在体内和体外的突触吞噬能力均受损。此外，我们证明TMEM59与C1q受体CD93相互作用,TMEM59缺乏促进小胶质细胞CD93蛋白降解.小胶质细胞中CD93的下调也损害了突触吞噬。这些发现确定了TMEM59在大脑发育过程中调节小胶质细胞功能对突触细化的关键作用，并表明TMEM59缺乏可能通过破坏兴奋性突触的吞噬作用从而扭曲兴奋性-抑制性（E/I）神经元活动平衡而导致ASD。意义声明小胶质细胞在突触细化中起重要作用。在大脑发育过程中，小胶质细胞的突触修剪失调与自闭症谱系障碍（ASD）有关。然而,潜在的机制尚未完全阐明。在这里，我们观察到跨膜蛋白59（TMEM59）的表达，自噬相关蛋白，在自闭症患者中减少。此外，我们发现在Tmem59完全缺失和小胶质细胞特异性缺失的小鼠中发生ASD样行为。机制研究表明,小胶质细胞中的TMEM59缺乏可能通过使C1q受体CD93不稳定而损害其突触吞噬能力,从而导致兴奋性神经传递增强和树突棘密度增加.我们的发现证明了小胶质细胞TMEM59在早期神经元发育中的关键作用，并为ASD的病因提供了新的见解。
