Taok1 haploinsufficiency leads to autistic-like behaviors in mice via the dorsal raphe nucleus
Jincheng Wang,
Weike Li,
Zimeng Li,
Zhenyu Xue,
Yuefang Zhang,
Yiting Yuan,
Yuhan Shi,
Shifang Shan,
Wenjian Han,
Fei Li,
Zilong Qiu
Affiliations
Jincheng Wang
Songjiang Research Institute, Songjiang District Central Hospital, Institute of Autism & MOE-Shanghai Key Laboratory for Children’s Environmental Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Institute of Neuroscience, Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China
Weike Li
Institute of Neuroscience, Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China
Zimeng Li
Institute of Neuroscience, Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China
Zhenyu Xue
Department of Anesthesiology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Yuefang Zhang
Songjiang Research Institute, Songjiang District Central Hospital, Institute of Autism & MOE-Shanghai Key Laboratory for Children’s Environmental Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Yiting Yuan
Songjiang Research Institute, Songjiang District Central Hospital, Institute of Autism & MOE-Shanghai Key Laboratory for Children’s Environmental Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Yuhan Shi
Institute of Neuroscience, Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China
Shifang Shan
Institute of Neuroscience, Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China
Wenjian Han
Songjiang Research Institute, Songjiang District Central Hospital, Institute of Autism & MOE-Shanghai Key Laboratory for Children’s Environmental Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Fei Li
MOE-Shanghai Key Laboratory for Children’s Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Zilong Qiu
Songjiang Research Institute, Songjiang District Central Hospital, Institute of Autism & MOE-Shanghai Key Laboratory for Children’s Environmental Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Institute of Neuroscience, Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China; MOE-Shanghai Key Laboratory for Children’s Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Clinic Neuroscience Center, Department of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, China; Corresponding author
Summary: Strong evidence from human genetic studies associates the thousand and one amino acid kinase 1 (TAOK1) gene with autism spectrum disorder (ASD). In this work, we discovered a de novo frameshifting mutation in TAOK1 within a Chinese ASD cohort. We found that Taok1 haploinsufficiency induces autistic-like behaviors in mice. Importantly, we observed a significant enrichment of Taok1 in the dorsal raphe nucleus (DRN). The haploinsufficiency of Taok1 considerably restrained the activation of DRN neurons during social interactions, leading to the aberrant phosphorylation of numerous proteins. Intriguingly, the genetic deletion of Taok1 in VGlut3-positive neurons of DRN resulted in mice exhibiting autistic-like behaviors. Ultimately, reintroducing wild-type Taok1, but not its kinase-dead variant, into the DRN of adult mice effectively mitigated the autistic-like behaviors associated with Taok1 haploinsufficiency. This work suggests that Taok1, through its influence in the DRN, regulates social interaction behaviors, providing critical insights into the etiology of ASD.
