Desipramine reverses remote memory deficits by activating calmodulin- CaMKII pathway in a UTX knockout mouse model of Kabuki syndrome  

作　　者：Lei Chen Yuting Li Minggang Liu Zhaohui Lan Xu Zhang Xiujuan Yang Qian Zhao Shuai Wang Longyong Xu Ying Zhou Yifang Kuang Tatsuo Suzuki Katsuhiko Tabuchi Eiki Takahashi Miou Zhou Charlie Degui Chen Tianle Xu Weidong Li 

机构地区：[1]Bio-X Institutes,Key Laboratory for the Genetics of Development and Neuropsychiatric Disorders(Ministry of Education),Brain Health and Brain Technology Center at Global Institute of Future Technology,Institute of Psychology and Behavioral Science,Shanghai Jiao Tong University,Shanghai,China [2]Department of Anatomy and Physiology,Shanghai Jiao Tong University School of Medicine,Shanghai,China [3]institute of Mental Health and Drug Discovery,Oujiang Laboratory,Wenzhou,Zhejiang,China [4]Shanghai Institutes for Biological Sciences,Chinese Academy of Sciences,Shanghai,China [5]Shinshu University School of Medicine,Nagano,Japan [6]western University of Health Sciences,Pomona,California,USA [7]WLA Laboratories,World Laureates Association,Shanghai,China

出　　处：《General Psychiatry》2024年第5期522-531,共10页综合精神医学（英文）

基　　金：supported by STI2030-Major Projects(2022ZD0204900);the National Natural Science Foundation of China(NSFC)(91632103,31900732,31771157);the Program of Shanghai Subject Chief Scientist(17XD1401700);National Key Research and Development Program of China(2018YFE0126700);the Shanghai Education Commission Research and Innovation Program(2019-01-07-00-02-E00037);Natural Science Foundation of Chongqing cstc2021jcyjmsxmX1176,the‘111’Program of Higher Education Discipline Innovation,‘Eastern Scholar’(Shanghai Municipal Education Commission),Shanghai Municipal Commission of Science and Technology Program(21dz2210100);China Postdoctoral Science Foundation(202N1702133,2021M702137);The National Science Fund for Distinguished Young Scholars(31900732).

摘　　要：Background Kabukisyndrome(KS)is arare developmental disorder characterised by multiple congenital anomalies and intellectual disability.UTX(ubiquitously transcribed tetratricopeptide repeat,X chromosome),which encodes a histone demethylase,is one of the two major pathogenic risk genes for KS.Although intellectual disability is a key phenotype of KS,the role of UTX in cognitive function remains unclear.Currently,no targeted therapies are available for KS.Aims This study aimed to investigate how UTX regulates cognition,to explore the mechanisms underlying UTX dysfunction and to identify potential molecular targets for treatment.Methods WegeneratedUTXconditional knockoutmice and found that UTX deletion downregulated calmodulin transcription by disrupting H3K27me3(trimethylated histone H3 at lysine 27)demethylation.Results UTX-knockout mice showeddecreased phosphorylation of calcium/calmodulin-dependent protein kinase I,impaired long-term potentiation and deficit in remote contextual fear memory.These effects were reversed by an Food and Drug Administration-approved drug desipramine.Conclusions Our results reveal an epigenetic mechanism underlying the important role of UTX in synaptic plasticity and cognitive function,and suggest that desipramine could be a potential treatment for KS.

关 键 词：IMPAIRED reversed UTX 

分 类 号：R749[医药卫生—神经病学与精神病学]