PI3K/AKT/mTOR-mediated autophagy in the development of autism spectrum disorder.
To investigate the association between PI3K/AKT/mTOR-mediated autophagy and the pathogenesis of autism spectrum disorder (ASD).



A sodium valproate (VPA)-induced baby rat model of ASD was built. Nine pregnant rats were randomly assigned into three groups, with three rats for each group: healthy control group, VPA group and mTOR inhibition group, receiving different drug administrations. Baby rats were grouped according to the maternal rats. Social interaction of baby rats (35days after birth) was observed and their bilateral hippocampes were sliced. We used electron microscope analysis for observation of autophagosome formation, double immunofluorescence staining for location of LC3 II, TUNEL assay for observation of cell apoptosis, Western Blot assay was used for measurement of LC3 II, P62, p53, Bcl-2, PI3K/AKT/mTOR-related proteins and p-S6.



VPA group had significantly lowered ability of social interaction than the control group and mTOR inhibition group (both P<0.05). The control group and the mTOTR inhibition group presented the visual of autophagosomes, while VPA group seldom had autophagosomes. By comparison with VPA group, mTOR group had a remarkable green fluorescence in the hippocampal CA1 (P<0.05). Western Blot assay revealved that mTOR inhibition group had a significantly higher LC3 II expression, higher LC3 II/LC3 I ratio, higher Bcl-2 expression and lower p53 than VPA group (all P<0.05). TUNEL assay showed that mTOR inhibition group had a significant smaller number of apoptotic cells in the hippocampal CA1. Besides, lowered expressions of p-PI3K, p-AKT and p-S6 were identified in the baby rats in mTOR inhibition group compared with VPA group (all P<0.05).



mTOR inhibition can increase PI3K/AKT/mTOR-mediated autophagic activity and improve social interaction in VPA-induced ASD, providing a novel target and direction for the treatment of ASD.
Department of Children's Rehabilitation, Linyi People's Hospital, Linyi, 276000 Shandong Province, PR China.
Jun
J
Zhang
Department of Clinical Psychology, Linyi People's Hospital, No. 27 Jiefang Road, Lanshan District, Linyi, 276000 Shandong Province, PR China. Electronic address: doctorjixiangzhang@163.com.
Ji-Xiang
JX
Zhang
Department of Children's Rehabilitation, Linyi People's Hospital, Linyi, 276000 Shandong Province, PR China.
Qin-Liang
QL
Zhang
D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D000067877:Autism Spectrum Disorder / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology* / Q000523:psychology; D001343:Autophagy / Q000187:drug effects / Q000502:physiology*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000633:toxicity; D005260:Female; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D008297:Male; D051058:Oncogene Protein v-akt / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000139:chemically induced / Q000503:physiopathology; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014635:Valproic Acid / Q000633:toxicity
D016207:Cytokines; D004791:Enzyme Inhibitors; D051058:Oncogene Protein v-akt; D019869:Phosphatidylinositol 3-Kinases; D010751:Phosphopyruvate Hydratase; D058570:TOR Serine-Threonine Kinases; D014635:Valproic Acid
Autism spectrum disorder; Autophagy; Cell apoptosis; PI3K/AKT/mTOR pathway; mTOR inhibition