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。

IF 5.3 3区 医学 Q1 PSYCHIATRY
General Psychiatry Pub Date : 2024-10-29 eCollection Date: 2024-01-01 DOI:10.1136/gpsych-2023-101430
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
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引用次数: 0

摘要

背景:歌舞伎综合征(KS)是一种罕见的发育障碍疾病,以多种先天性畸形和智力障碍为特征。UTX(泛转录四肽重复,X 染色体)编码组蛋白去甲基化酶,是 KS 的两大致病风险基因之一。虽然智力障碍是 KS 的主要表型,但UTX 在认知功能中的作用仍不清楚。目的:本研究旨在研究UTX如何调节认知,探索UTX功能障碍的机制,并确定潜在的治疗分子靶点:我们产生了UTX条件性基因敲除小鼠,发现UTX缺失通过破坏H3K27me3(三甲基化组蛋白H3赖氨酸27)的去甲基化下调钙调蛋白转录:结果:UTX基因敲除小鼠表现出钙/钙调蛋白依赖性蛋白激酶II磷酸化减少、长期延时能力受损以及远距离情境恐惧记忆缺失。食品与药物管理局批准的药物地西帕明可逆转这些影响:我们的研究结果揭示了UTX在突触可塑性和认知功能中发挥重要作用的表观遗传学机制,并表明地西泮可能是治疗KS的一种潜在方法。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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.

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来源期刊
General Psychiatry
General Psychiatry 医学-精神病学
CiteScore
21.90
自引率
2.50%
发文量
848
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.
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