title: Valproic acid exposure sequentially activates Wnt and mTOR pathways in rats.
abstract: Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impaired social interaction, limited verbal communication and repetitive behaviors. Recent studies have demonstrated that Wnt signaling and mTOR signaling play important roles in the pathogenesis of ASD. However, the relationship of these two signaling pathways in ASD remains unclear.
  
  
  
  We assessed this question using the valproic acid (VPA) rat model of autism. Our results demonstrated that VPA exposure activated mTOR signaling and suppressed autophagy in the prefrontal cortex, hippocampus and cerebellum of autistic model rats, characterized by enhanced phospho-mTOR and phospho-S6 and decreased Beclin1, Atg5, Atg10, LC3-II and autophagosome formation. Rapamycin treatment suppressed the effect of VPA on mTOR signaling and ameliorated the autistic-like behaviors of rats in our autism model. The administration of VPA also activated Wnt signaling through up-regulating beta-catenin and phospho-GSK3beta. Suppression of the Wnt pathway by sulindac relieved autistic-like behaviors and attenuated VPA-induced mTOR signaling activation in autistic model rats.
  
  
  
  Our results demonstrate that VPA exposure sequentially activates Wnt signaling and mTOR signaling in rats. Suppression of the Wnt signaling pathway relieves autistic-like behaviors partially by deactivating the mTOR signaling pathway in VPA-exposed rats.
authors.affiliation: Chongqing Key Laboratory of Psychological Diagnosis and Educational Technology for Children with Special Needs, Chongqing 400047, China; Department of Blood Transfusion, Southwest Hospital of Third Military Medical University,Chongqing 400038, China.
authors.forename: Liyan
authors.initials: L
authors.lastname: Qin
authors.affiliation: Chongqing Key Laboratory of Psychological Diagnosis and Educational Technology for Children with Special Needs, Chongqing 400047, China; College of Education Science, Chongqing Normal University, Chongqing 400047, China. Electronic address: xufangd@aliyun.com.
authors.forename: Xufang
authors.initials: X
authors.lastname: Dai
authors.affiliation: Guizhou Minzu University, Guiyang 550025, China.
authors.forename: Yunhou
authors.initials: Y
authors.lastname: Yin
mesh_terms: D000818:Animals; D000067877:Autism Spectrum Disorder / Q000209:etiology / Q000378:metabolism; D000071182:Autophagosomes / Q000378:metabolism; D018682:GABA Agents / Q000494:pharmacology* / Q000633:toxicity; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism; D008297:Male; D017397:Prefrontal Cortex / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014635:Valproic Acid / Q000494:pharmacology* / Q000633:toxicity; D060449:Wnt Signaling Pathway
chemical_list: D018682:GABA Agents; D014635:Valproic Acid; D000071679:Glycogen Synthase Kinase 3 beta; D058570:TOR Serine-Threonine Kinases
keywords: Autism spectrum disorder; Autophagy; VPA; Wnt; mTOR