自闭症
前额叶皮质
神经科学
心理学
UBE3A公司
自闭症谱系障碍
发育障碍
树突棘
焦虑
神经发育障碍
边缘下皮质
基因
发展心理学
精神科
生物
遗传学
认知
泛素连接酶
泛素
海马结构
作者
Yongxia Li,Zhi-Nei Tan,Xu-Hui Li,Berlina Ma,Frank Adu Nti,Xiafu Lv,Zhenjun Tian,Riqiang Yan,Heng‐Ye Man,Xin−Ming Ma
标识
DOI:10.1038/s41380-024-02515-7
摘要
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impaired social interactions, communication deficits and repetitive behaviors. A study of autistic human subjects has identified RFWD2 as a susceptibility gene for autism, and autistic patients have 3 copies of the RFWD2 gene. The role of RFWD2 as an E3 ligase in neuronal functions, and its contribution to the pathophysiology of ASD, remain unknown. We generated RFWD2 knockin mice to model the human autistic condition of high gene dosage of RFWD2. We found that heterozygous knockin (Rfwd2+/-) male mice exhibited the core symptoms of autism. Rfwd2+/- male mice showed deficits in social interaction and communication, increased repetitive and anxiety-like behavior, and spatial memory deficits, whereas Rfwd2+/- female mice showed subtle deficits in social communication and spatial memory but were normal in anxiety-like, repetitive, and social behaviors. These autistic-like behaviors in males were accompanied by a reduction in dendritic spine density and abnormal synaptic function on layer II/III pyramidal neurons in the prelimbic area of the medial prefrontal cortex (mPFC), as well as decreased expression of synaptic proteins. Impaired social behaviors in Rfwd2+/- male mice were rescued by the expression of ETV5, one of the major substrates of RFWD2, in the mPFC. These findings indicate an important role of RFWD2 in the pathogenesis of autism.
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