小胶质细胞介导的神经炎症和突触修剪参与自闭症谱系障碍的研究进展

Progress in microglia-mediated neuroinflammation and synaptic pruning in autism spectrum disorder

[背景]自闭症谱系障碍(ASD)是一类以社会交往缺陷和重复刻板行为为特征的神经发育障碍.许多遗传因素和环境因素可导致ASD的发生,但ASD明确的致病机制仍不清楚.[进展]近年来,小胶质细胞在ASD中的作用受到越来越多的关注,大量证据表明小胶质细胞在突触形成和ASD疾病发展过程中发挥重要作用.本文根据ASD患者临床样本和ASD动物模型中关于小胶质细胞的研究进展,详细综述了ASD中小胶质细胞介导的神经炎症反应和对突触功能的调控作用.[展望]ASD中小胶质细胞功能为何发生异常以及小胶质细胞如何参与ASD的发生发展仍需进一步探究.小胶质细胞中参与ASD的风险因子有待鉴定,小胶质细胞功能异常影响ASD进程的分子机制也急需阐释.这些将有助于更深入了解小胶质细胞功能异常与ASD之间的联系,从而为ASD的临床诊断和治疗策略提供依据.

[Background]Autism spectrum disorder(ASD)is a group of neurodevelopmental disorders characterized by deficits in social interactions and repetitive behaviors,accompanied by some related issues such as intellectual disability,anxiety,depression,sleep deficits,attention deficit and hyperactivity disorder,seizures,and obsessive-compulsive disorder.A large number of studies have shown that various genetic,epigenetic modification and environmental factors contribute to the etiology and development of ASD.However,the precise mechanisms underlying ASD have yet to be elucidated.[Progress]In recent years,the role of microglia in ASD has received increasing attention.Microglia not only mediate neuroinflammation in response to stimulus but also regulate brain development and neural circuits through synaptic pruning.Microglial activation and increased neuroinflammation have been observed in both ASD postmortem brain tissues and animal models,suggesting that the activation of microglia may contribute to the pathology and behavioral abnormalities of ASD.Moreover,increasing evidence suggests that abnormal microglia also contribute to ASD through dysregulating synaptic formation.Although microglia are found to be aberrantly activated in the ASD brain,dendritic spine density is found to be higher in ASD patients than that in control healthy group.The increased spine density may be attributed to the reduced capacity of synaptic pruning by microglia.Several molecular signals,such as complement pathways,triggering receptor expressed on myeloid cells 2(TREM2)and C-X3-C motif chemokine receptor 1-ligand 1(CX3CR1-CX3CL1)axis,participate in microglial synaptic pruning and are found to be abnormally expressed in the individuals with ASD.Previous studies have demonstrated that dysregulation of these signals leads to impaired synaptic pruning and ASD-like behaviors in mice.However,whether there is a direct association between microglia-mediated neuroinflammation and synaptic pruning remains to be explored.This comprehensive review summarizes the current findings about microglia-mediated neuroinflammation and synaptic function in ASD.[Perspective]The etiology of ASD is not solely attributed to neuronal abnormality.Emerging evidence indicates that microglial dysfunction also plays a crucial role in the etiology and development of ASD.Abnormal activation of microglia and increased neuroinflammation are found in the brains of patients with ASD and contribute to the development of the disease.Synaptic pruning by microglia is necessary for synaptic maturation and plasticity during the early brain neurodevelopment.Aberrant synaptic pruning in ASD can also lead to changes in the number and function of synapses.This review provides a deeper understanding of the association between microglial dysfunction and ASD.So far,the correlation between neuroinflammatory responses and the abnormal synaptic regulation mediated by microglia in ASD remains uncertain and requires detailed investigation.Further study on the molecular mechanisms underlying microglia dysfunction-induced ASD,such as identifying risk genes of ASD in microglia using modern techniques like single-cell sequencing,will provide better guidance for the clinical diagnosis and therapeutic strategy for ASD.