Zheng Wei'an, Wang Mengmeng, Cui Yi, Xu Qing, Chen Yujiang, Xian Panpan, Yang Qinghu, Wu Shengxi, Wang Yazhou
School of Life Science, Research Center for Resource Peptide Drugs, Shaanxi Engineering and Technological Research Center for Conversation and Utilization of Regional Biological Resources, Yanan University, Yanan, 716000, PR China.
Department of Neurobiology and Institute of Neurosciences, School of Basic Medicine, Fourth Military Medical University, Xi'an, Shaanxi 710032, PR China.
Heliyon. 2024 May 6;10(9):e30617. doi: 10.1016/j.heliyon.2024.e30617. eCollection 2024 May 15.
Autism spectrum disorder (ASD) is a group of developmental diseases characterized by social dysfunction and repetitive stereotype behaviors. Besides genetic mutations, environmental factors play important roles in the development of ASD. Valproic acid (VPA) is widely used for modeling environmental factor induced ASD in rodents. However, traditional VPA modeling is low-in-efficiency and the phenotypes often vary among different batches of experiments. To optimize this ASD-modeling method, we tested "two-hit" hypothesis by single or double exposure of VPA and poly:IC at the critical time points of embryonic and postnatal stage. The autistic-like behaviors of mice treated with two-hit schemes (embryonic VPA plus postnatal poly:IC, embryonic poly:IC plus postnatal VPA, embryonic VPA plus poly: IC, or postnatal VPA plus poly:IC) were compared with mice treated with traditional VPA protocol. The results showed that all single-hit and two-hit schemes produced core ASD phenotypes as VPA single treatment did. Only one group, namely, mice double-hit by VPA and poly:IC simultaneously at E12.5 showed severe impairment of social preference, social interaction and ultrasonic communication, as well as significant increase of grooming activity and anxiety-like behaviors, in comparation with mice treated with the traditional VPA protocol. These data demonstrated that embryonic two-hit of VPA and poly:IC is more efficient in producing ASD phenotypes in mice than the single-hit of VPA, indicating this two-hit scheme could be utilized for modeling environmental factors induced ASD.
自闭症谱系障碍（ASD）是一组以社交功能障碍和重复刻板行为为特征的发育性疾病。除基因突变外，环境因素在ASD的发生发展中也起着重要作用。丙戊酸（VPA）被广泛用于在啮齿动物中模拟环境因素诱导的ASD。然而，传统的VPA建模效率低下，且不同批次实验的表型往往存在差异。为了优化这种ASD建模方法，我们在胚胎期和出生后阶段的关键时间点通过单次或两次暴露VPA和聚肌胞苷酸（poly:IC）来测试“双打击”假说。将采用双打击方案（胚胎期VPA加出生后poly:IC、胚胎期poly:IC加出生后VPA、胚胎期VPA加poly:IC或出生后VPA加poly:IC）处理的小鼠的自闭症样行为与采用传统VPA方案处理的小鼠进行比较。结果表明，所有单次打击和双打击方案都产生了与VPA单一处理相同的核心ASD表型。与采用传统VPA方案处理的小鼠相比，只有一组，即E12.5时同时受到VPA和poly:IC双打击的小鼠，表现出社交偏好、社交互动和超声通讯的严重受损，以及梳理行为和焦虑样行为的显著增加。这些数据表明，胚胎期VPA和poly:IC双打击在小鼠中产生ASD表型比VPA单次打击更有效，表明这种双打击方案可用于模拟环境因素诱导的ASD。
