{"title":"在UTX基因敲除的歌舞伎综合征小鼠模型中,地西泮通过激活钙调蛋白-CaMKII通路逆转遥感记忆缺陷。","authors":"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","doi":"10.1136/gpsych-2023-101430","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Kabuki syndrome (KS) is a rare developmental disorder characterised by multiple congenital anomalies and intellectual disability. <i>UTX</i> (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 <i>UTX</i> in cognitive function remains unclear. Currently, no targeted therapies are available for KS.</p><p><strong>Aims: </strong>This study aimed to investigate how <i>UTX</i> regulates cognition, to explore the mechanisms underlying <i>UTX</i> dysfunction and to identify potential molecular targets for treatment.</p><p><strong>Methods: </strong>We generated <i>UTX</i> conditional knockout mice and found that <i>UTX</i> deletion downregulated calmodulin transcription by disrupting H3K27me3 (trimethylated histone H3 at lysine 27) demethylation.</p><p><strong>Results: </strong><i>UTX</i>-knockout mice showed decreased phosphorylation of calcium / calmodulin-dependent protein kinase II, impaired long-term potentiation and deficit in remote contextual fear memory. These effects were reversed by an Food and Drug Administration-approved drug desipramine.</p><p><strong>Conclusions: </strong>Our results reveal an epigenetic mechanism underlying the important role of <i>UTX</i> in synaptic plasticity and cognitive function, and suggest that desipramine could be a potential treatment for KS.</p>","PeriodicalId":12549,"journal":{"name":"General Psychiatry","volume":null,"pages":null},"PeriodicalIF":5.3000,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11529476/pdf/","citationCount":"0","resultStr":"{\"title\":\"Desipramine reverses remote memory deficits by activating calmodulin-CaMKII pathway in a UTX knockout mouse model of Kabuki syndrome.\",\"authors\":\"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\",\"doi\":\"10.1136/gpsych-2023-101430\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Kabuki syndrome (KS) is a rare developmental disorder characterised by multiple congenital anomalies and intellectual disability. <i>UTX</i> (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 <i>UTX</i> in cognitive function remains unclear. Currently, no targeted therapies are available for KS.</p><p><strong>Aims: </strong>This study aimed to investigate how <i>UTX</i> regulates cognition, to explore the mechanisms underlying <i>UTX</i> dysfunction and to identify potential molecular targets for treatment.</p><p><strong>Methods: </strong>We generated <i>UTX</i> conditional knockout mice and found that <i>UTX</i> deletion downregulated calmodulin transcription by disrupting H3K27me3 (trimethylated histone H3 at lysine 27) demethylation.</p><p><strong>Results: </strong><i>UTX</i>-knockout mice showed decreased phosphorylation of calcium / calmodulin-dependent protein kinase II, impaired long-term potentiation and deficit in remote contextual fear memory. These effects were reversed by an Food and Drug Administration-approved drug desipramine.</p><p><strong>Conclusions: </strong>Our results reveal an epigenetic mechanism underlying the important role of <i>UTX</i> in synaptic plasticity and cognitive function, and suggest that desipramine could be a potential treatment for KS.</p>\",\"PeriodicalId\":12549,\"journal\":{\"name\":\"General Psychiatry\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":5.3000,\"publicationDate\":\"2024-10-29\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11529476/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"General Psychiatry\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1136/gpsych-2023-101430\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/1/1 0:00:00\",\"PubModel\":\"eCollection\",\"JCR\":\"Q1\",\"JCRName\":\"PSYCHIATRY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"General Psychiatry","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1136/gpsych-2023-101430","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/1/1 0:00:00","PubModel":"eCollection","JCR":"Q1","JCRName":"PSYCHIATRY","Score":null,"Total":0}
Desipramine reverses remote memory deficits by activating calmodulin-CaMKII pathway in a UTX knockout mouse model of Kabuki syndrome.
Background: Kabuki syndrome (KS) is a rare 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: We generated UTX conditional knockout mice and found that UTX deletion downregulated calmodulin transcription by disrupting H3K27me3 (trimethylated histone H3 at lysine 27) demethylation.
Results: UTX-knockout mice showed decreased phosphorylation of calcium / calmodulin-dependent protein kinase II, 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.
期刊介绍:
General Psychiatry (GPSYCH), an open-access journal established in 1959, has been a pioneer in disseminating leading psychiatry research. Addressing a global audience of psychiatrists and mental health professionals, the journal covers diverse topics and publishes original research, systematic reviews, meta-analyses, forums on topical issues, case reports, research methods in psychiatry, and a distinctive section on 'Biostatistics in Psychiatry'. The scope includes original articles on basic research, clinical research, community-based studies, and ecological studies, encompassing a broad spectrum of psychiatric interests.