Establishment of a two-hit mouse model of environmental factor induced autism spectrum disorder
Wei'an Zheng,
Mengmeng Wang,
Yi Cui,
Qing Xu,
Yujiang Chen,
Panpan Xian,
Qinghu Yang,
Shengxi Wu,
Yazhou Wang
Affiliations
Wei'an Zheng
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
Mengmeng Wang
Department of Neurobiology and Institute of Neurosciences, School of Basic Medicine, Fourth Military Medical University, Xi'an, Shaanxi 710032, PR China
Yi Cui
Dalian Rehabilitation Recuperation Center of Joint Logistics Support Force of PLA, No.30, Binhaixiroad, Xigang District, Dalian, 116013, PR China
Qing Xu
Department of Neurobiology and Institute of Neurosciences, School of Basic Medicine, Fourth Military Medical University, Xi'an, Shaanxi 710032, PR China
Yujiang Chen
State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Clinical Research Center for Oral Diseases, Department of Pediatric Dentistry, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, PR China
Panpan Xian
Department of Neurobiology and Institute of Neurosciences, School of Basic Medicine, Fourth Military Medical University, Xi'an, Shaanxi 710032, PR China
Qinghu Yang
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; Corresponding author. Research Center for Resource Peptide Drugs, School of life Science, Yan'an University, Shannxi, Yan'an, 716000, PR China.
Shengxi Wu
Department of Neurobiology and Institute of Neurosciences, School of Basic Medicine, Fourth Military Medical University, Xi'an, Shaanxi 710032, PR China; Corresponding author. Department of Neurobiology and Institute of Neurosciences, School of Basic Medicine, Fourth Military Medical University, Xi’an, Shaanxi, 710032, PR China.
Yazhou Wang
Department of Neurobiology and Institute of Neurosciences, School of Basic Medicine, Fourth Military Medical University, Xi'an, Shaanxi 710032, PR China; Corresponding author. Department of Neurobiology and Institute of Neurosciences, School of Basic Medicine, Fourth Military Medical University, Xi’an, Shaanxi, 710032, PR China.
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.
