TREM2 improves microglia function and synaptic development in autism spectrum disorders by regulating P38 MAPK signaling pathway.

IF 3.3 3区医学 Q2 NEUROSCIENCES

Molecular Brain Pub Date : 2024-02-26 DOI:10.1186/s13041-024-01081-x

Yi Tian, Xiao Xiao, Weiliang Liu, Shanqing Cheng, Na Qian, Ling Wang, Yang Liu, Rong Ai, Xiaoping Zhu

{"title":"TREM2 improves microglia function and synaptic development in autism spectrum disorders by regulating P38 MAPK signaling pathway.","authors":"Yi Tian, Xiao Xiao, Weiliang Liu, Shanqing Cheng, Na Qian, Ling Wang, Yang Liu, Rong Ai, Xiaoping Zhu","doi":"10.1186/s13041-024-01081-x","DOIUrl":null,"url":null,"abstract":"Background: Autism spectrum disorder (ASD) encompasses a diverse range of neurodevelopmental disorders, but the precise underlying pathogenesis remains elusive. This study aim to explore the potential mechanism of TREM2 in regulating microglia function in ASD.Materials and methods: The offspring rat model of ASD was established through prenatal exposure to valproic acid (VPA), and the behavioral symptoms of the ASD model were observed. On postnatal day (PND) 7 and PND 28, the effects of prenatally exposure to VPA on synaptic development and microglia phenotype of offspring rats were observed. Primary microglia were cultured in vitro. Lentivirus and adenovirus were utilized to interfere with TREM2 and overexpress TREM2.Results: Prenatally VPA exposure induced offspring rats to show typical ASD core symptoms, which led to abnormal expression of synapse-related proteins in the prefrontal cortex of offspring rats, changed the phenotype of microglia in offspring rats, promoted the polarization of microglia to pro-inflammatory type, and increased inflammatory response. The experimental results in vitro showed that overexpression of TREM2 could increase the expression of Gephyrin, decrease the content of CD86 protein and increase the content of CD206 protein. In addition, after the expression of TREM2 was interfered, the content of p-P38 MAPK protein increased and the content of p-ELK-1 protein decreased.Conclusion: The protective influence of TREM2 on the VPA-induced ASD model is attributed to its inhibition of the P38 MAPK pathway, this protective effect may be achieved by promoting the polarization of microglia to anti-inflammatory phenotype and improving the neuronal synaptic development.","PeriodicalId":18851,"journal":{"name":"Molecular Brain","volume":null,"pages":null},"PeriodicalIF":3.3000,"publicationDate":"2024-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10898105/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular Brain","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1186/s13041-024-01081-x","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"NEUROSCIENCES","Score":null,"Total":0}

引用次数: 0

Abstract

Background: Autism spectrum disorder (ASD) encompasses a diverse range of neurodevelopmental disorders, but the precise underlying pathogenesis remains elusive. This study aim to explore the potential mechanism of TREM2 in regulating microglia function in ASD.

Materials and methods: The offspring rat model of ASD was established through prenatal exposure to valproic acid (VPA), and the behavioral symptoms of the ASD model were observed. On postnatal day (PND) 7 and PND 28, the effects of prenatally exposure to VPA on synaptic development and microglia phenotype of offspring rats were observed. Primary microglia were cultured in vitro. Lentivirus and adenovirus were utilized to interfere with TREM2 and overexpress TREM2.

Results: Prenatally VPA exposure induced offspring rats to show typical ASD core symptoms, which led to abnormal expression of synapse-related proteins in the prefrontal cortex of offspring rats, changed the phenotype of microglia in offspring rats, promoted the polarization of microglia to pro-inflammatory type, and increased inflammatory response. The experimental results in vitro showed that overexpression of TREM2 could increase the expression of Gephyrin, decrease the content of CD86 protein and increase the content of CD206 protein. In addition, after the expression of TREM2 was interfered, the content of p-P38 MAPK protein increased and the content of p-ELK-1 protein decreased.

Conclusion: The protective influence of TREM2 on the VPA-induced ASD model is attributed to its inhibition of the P38 MAPK pathway, this protective effect may be achieved by promoting the polarization of microglia to anti-inflammatory phenotype and improving the neuronal synaptic development.

查看原文本刊更多论文

TREM2 通过调节 P38 MAPK 信号通路改善自闭症谱系障碍中的小胶质细胞功能和突触发育。

背景：自闭症谱系障碍（ASD）包括多种神经发育障碍，但其确切的潜在发病机制仍难以确定。本研究旨在探讨 TREM2 在 ASD 中调节小胶质细胞功能的潜在机制：通过产前暴露于丙戊酸（VPA）建立ASD后代大鼠模型，并观察ASD模型的行为症状。在出生后第7天和第28天，观察产前暴露于VPA对后代大鼠突触发育和小胶质细胞表型的影响。体外培养原代小胶质细胞。利用慢病毒和腺病毒干扰TREM2和过表达TREM2：结果：胎儿期VPA暴露诱导子代大鼠出现典型的ASD核心症状，导致子代大鼠前额叶皮层突触相关蛋白表达异常，改变了子代大鼠小胶质细胞的表型，促进小胶质细胞极化为促炎型，增加了炎症反应。体外实验结果表明，过表达 TREM2 可增加 Gephyrin 的表达，降低 CD86 蛋白的含量，增加 CD206 蛋白的含量。此外，干扰TREM2的表达后，p-P38 MAPK蛋白含量增加，p-ELK-1蛋白含量减少：结论：TREM2对VPA诱导的ASD模型的保护作用归因于其对P38 MAPK通路的抑制，这种保护作用可能是通过促进小胶质细胞向抗炎表型极化和改善神经元突触发育来实现的。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Molecular Brain NEUROSCIENCES-

CiteScore

7.30

自引率

0.00%

发文量

审稿时长

>12 weeks

期刊介绍： Molecular Brain is an open access, peer-reviewed journal that considers manuscripts on all aspects of studies on the nervous system at the molecular, cellular, and systems level providing a forum for scientists to communicate their findings. Molecular brain research is a rapidly expanding research field in which integrative approaches at the genetic, molecular, cellular and synaptic levels yield key information about the physiological and pathological brain. These studies involve the use of a wide range of modern techniques in molecular biology, genomics, proteomics, imaging and electrophysiology.