School of Pediatrics, Guizhou Medical University, Guiyang City, China.
Department of Pediatrics, The Affiliated Hospital of Guizhou Medical University, No. 28 Guiyi Street, Yunyan District, 550004, Guiyang City, China.
Mol Brain. 2024 Feb 26;17(1):12. doi: 10.1186/s13041-024-01081-x.
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.
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.
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.
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.
自闭症谱系障碍（ASD）包含一系列神经发育障碍，但确切的潜在发病机制仍难以捉摸。本研究旨在探讨 TREM2 调节 ASD 中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 仔鼠模型，并观察 ASD 模型的行为症状。在出生后第 7 天（PND7）和第 28 天（PND28），观察 VPA 产前暴露对仔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 并过表达 TREM2。
产前 VPA 暴露使仔鼠表现出典型的 ASD 核心症状，导致仔鼠前额叶皮质中突触相关蛋白表达异常，改变仔鼠小胶质细胞表型，促进小胶质细胞向促炎型极化，增加炎症反应。体外实验结果表明，过表达 TREM2 可增加 Gephyrin 的表达，降低 CD86 蛋白含量，增加 CD206 蛋白含量。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。
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。
