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

作者全名："Wang, Luyi; Xu, Man; Wang, Yan; Wang, Feifei; Deng, Jing; Wang, Xiaoya; Zhao, Yu; Liao, Ailing; Yang, Feng; Wang, Shali; Li, Yingbo"

作者地址："[Wang, Luyi; Xu, Man; Wang, Yan; Wang, Feifei; Deng, Jing; Wang, Xiaoya; Zhao, Yu; Liao, Ailing; Wang, Shali; Li, Yingbo] Chongqing Med Univ, Inst Neurosci, Sch Basic Med Sci, Dept Physiol, Chongqing, Peoples R China; [Xu, Man] Chongqing Univ, Dept Pediat, Fuling Hosp, Chongqing, Peoples R China; [Deng, Jing] Army Med Univ, Xinqiao Hosp, Dept Neurosurg, Chongqing, Peoples R China; [Wang, Xiaoya] Affiliated Hosp, North Sichuan Med Coll, Dept Pathol, Nanchong, Sichuan, Peoples R China; [Liao, Ailing] Chongqing Populat & Family Planning Sci & Technol, NHC Key Lab Birth Defects & Reprod Hlth, Chongqing, Peoples R China; [Yang, Feng] Capital Med Univ, Beijing Tiantan Hosp, China Natl Clin Res Ctr Neurol Dis, Beijing, Peoples R China; [Yang, Feng] Capital Med Univ, Adv Innovat Ctr Human Brain Protect, Beijing, Peoples R China"

通信作者："Wang, SL; Li, YB (通讯作者)，Chongqing Med Univ, Inst Neurosci, Sch Basic Med Sci, Dept Physiol, Chongqing, Peoples R China."

来源：NEURAL REGENERATION RESEARCH

ESI学科分类：NEUROSCIENCE & BEHAVIOR

WOS号：WOS:001107628900007

JCR分区：Q1

影响因子：5.9

年份：2024

卷号：19

期号：7

开始页：1618

结束页：1624

文献类型：Article

关键词：autism; Ctnnd2 deletion; GABAergic neurons; melatonin; PI3K/Akt signal pathway; prefrontal cortex; social behavior; spine density; synaptic-associated proteins

摘要："Autism spectrum disorders are a group of neurodevelopmental disorders involving more than 1100 genes, including Ctnnd2 as a candidate gene. Ctnnd2 knockout mice, serving as an animal model of autism, have been demonstrated to exhibit decreased density of dendritic spines. The role of melatonin, as a neurohormone capable of effectively alleviating social interaction deficits and regulating the development of dendritic spines, in Ctnnd2 deletion-induced nerve injury remains unclear. In the present study, we discovered 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 prefrontal 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, wortmannin, 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 GABAergic synaptic function by activating the PI3K/Akt signal pathway, which may contribute to the improvement of dendritic spine abnormalities in autism spectrum disorders."

基金机构："Chongqing Science and Technology Committee, Natural Science Foundation of Chongqing [cstc2021jcyj-msxmX0065]"

基金资助正文："This study was supported by the Chongqing Science and Technology Committee, Natural Science Foundation of Chongqing, No. cstc2021jcyj-msxmX0065 (to YL)"