Melatonin improves synapse development by PI3K/Akt signaling in a mouse model of autism spectrum disorder  

作　　者：Luyi Wang Man Xu Yan Wang Feifei Wang Jing Deng Xiaoya Wang Yu Zhao Ailing Liao Feng Yang Shali Wang Yingbo Li 

机构地区：[1]Institute of Neuroscience,Department of Physiology,School of Basic Medical Science,Chongqing Medical University,Chongqing,China [2]Department of Pediatric,Chongqing University Fuling Hospital,Chongqing,China [3]Department of Neurosurgery,Xinqiao Hospital,Army Medical University,Chongqing,China [4]Department of Pathology,Affiliated Hospital of North Sichuan Medical College,Nanchong,Sichuan Province,China [5]NHC Key Laboratory of Birth Defects and Reproductive Health,Chongqing Population and Family Planning Science and Technology Research Institute,Chongqing,China [6]China National Clinical Research Center for Neurological Diseases,Beijing Tiantan Hospital,Capital Medical University,Beijing,China [7]Advanced Innovation Center for Human Brain Protection,Capital Medical University,Beijing,China

出　　处：《Neural Regeneration Research》2024年第7期1618-1624,共7页中国神经再生研究（英文版）

基　　金：supported by the Chongqing Science and Technology Committee;Natural Science Foundation of Chongqing,No.cstc2021jcyj-msxmX0065 (to YL)。

摘　　要：Autism spectrum disorders are a group of neurodevelopmental disorders involving more than 1100 genes,including Ctnnd2 as a candidate gene.Ctnnd2knockout mice,serving as an animal model of autis m,have been demonstrated to exhibit decreased density of dendritic spines.The role of melatonin,as a neuro hormone capable of effectively alleviating social interaction deficits and regulating the development of dendritic spines,in Ctnnd2 deletion-induced nerve injury remains unclea r.In the present study,we discove red that the deletion of exon 2 of the Ctnnd2 gene was linked to social interaction deficits,spine loss,impaired inhibitory neurons,and suppressed phosphatidylinositol-3-kinase(PI3K)/protein kinase B(Akt) signal pathway in the prefrontal cortex.Our findings demonstrated that the long-term oral administration of melatonin for 28 days effectively alleviated the aforementioned abnormalities in Ctnnd2 gene-knockout mice.Furthermore,the administration of melatonin in the prefro ntal cortex was found to improve synaptic function and activate the PI3K/Akt signal pathway in this region.The pharmacological blockade of the PI3K/Akt signal pathway with a PI3K/Akt inhibitor,wo rtmannin,and melatonin receptor antagonists,luzindole and 4-phenyl-2-propionamidotetralin,prevented the melatonin-induced enhancement of GABAergic synaptic function.These findings suggest that melatonin treatment can ameliorate GABAe rgic synaptic function by activating the PI3K/Akt signal pathway,which may contribute to the improvement of dendritic spine abnormalities in autism spectrum disorders.

关 键 词：AUTISM Ctnnd2 deletion GABAergic neurons MELATONIN PI3K/Akt signal pathway prefrontal cortex social behavior spine density synaptic-associated proteins 

分 类 号：R749.94[医药卫生—神经病学与精神病学] R-332[医药卫生—临床医学]