School of Life Sciences, Shanghai University, Shanghai 200444, PR China.
Department of Laboratory Animal Science, Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China.
Behav Brain Res. 2022 Jun 25;428:113888. doi: 10.1016/j.bbr.2022.113888. Epub 2022 Apr 8.
Autism is a complex neurodevelopmental disease that may be caused by genetic and environmental factors, that are incompletely understood. Overactivation of dopaminergic receptors can lead to autistic-like behavior. β-arrestin2 (Arrb2) is a scaffolding protein of the arrestin family, which function as cytosolic multifunctional adapter proteins that activate cell signal transduction and mediate the signal termination and endocytosis of G-protein-coupled receptors (GPCRs) complexes. In this study, we established an Arrb2 knockout (Arrb2) mouse to explore the biological function of Arrb2 in autistic-like behavior caused by abnormality in the dopaminergic system. We found that Arrb2 mice did not exhibit the autistic-like behavior normally induced by SKF38393, an agonist of the dopamine receptor 1 (D1R). Compared with wild-type (WT) untreated mice, the SKF38393-treated WT mice and Arrb2 mice, with or without SKF38393 treatment, showed abnormalities on electroencephalography (EEG) and increased stimulation of the phosphorylated form of extracellular signal-regulated kinase (p-ERK) via the PKA/Rap1/B-Raf/MEK pathway. These results demonstrated that Arrb2 regulated the dopaminergic system through the ERK signaling pathway in the occurrence and development of autism, and that targeted deletion of Arrb2 impeded the development of autistic-like behavior.
自闭症是一种复杂的神经发育性疾病，可能由遗传和环境因素引起，但这些因素尚未完全阐明。多巴胺能受体的过度激活可能导致类似自闭症的行为。β-arrestin2（Arrb2）是一种 arrestin 家族的支架蛋白，作为细胞溶质多功能衔接蛋白，激活细胞信号转导，并介导 G 蛋白偶联受体（GPCR）复合物的信号终止和内化。在这项研究中，我们建立了 Arrb2 敲除（Arrb2）小鼠，以探索 Arrb2 在多巴胺能系统异常引起的类似自闭症行为中的生物学功能。我们发现，Arrb2 小鼠不会表现出多巴胺受体 1（D1R）激动剂 SKF38393 通常诱导的类似自闭症行为。与未经处理的野生型（WT）小鼠相比，SKF38393 处理的 WT 小鼠和 Arrb2 小鼠，无论是否接受 SKF38393 处理，脑电图（EEG）均出现异常，并通过 PKA/Rap1/B-Raf/MEK 途径增加细胞外信号调节激酶（p-ERK）的磷酸化形式的刺激。这些结果表明，Arrb2 通过 ERK 信号通路调节自闭症的发生和发展中的多巴胺能系统，靶向敲除 Arrb2 会阻碍类似自闭症行为的发展。
