Zfp804a条件性基因敲除小鼠的精神分裂症样缺陷和谷氨酸/γ-氨基丁酸稳态受损

IF 5.3 1区 医学 Q1 PSYCHIATRY
Qiao-Xia Zhang, Shan-Shan Wu, Peng-Jie Wang, Rui Zhang, Robert K Valenzuela, Shan-Shan Shang, Ting Wan, Jie Ma
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引用次数: 0

摘要

背景与假设:锌指蛋白804A(ZNF804A)是第一个与精神分裂症(SCZ)相关的全基因组易感基因,通过影响神经发育调控、神经元外生、突触可塑性和RNA翻译控制,在SCZ的病理生理学中发挥着重要作用;然而,确切的分子机制仍不清楚:研究设计:利用聚类规律性间隔短回文重复/Cas9技术和Cre/loxP方法产生了神经系统特异性Zfp804a(ZNF804A鼠基因)条件性基因敲除(cKO)小鼠模型:结果:在Zfp804a cKO小鼠中观察到多种复杂的SCZ样行为,如焦虑、抑郁和认知障碍。分子生物学方法和靶向代谢组学检测证实,Zfp804a cKO小鼠皮质中SATB2(皮质浅层神经元标志物)的表达发生了改变;海马中异常的 NeuN、裂解的 Caspase 3 和 DLG4(分别是成熟神经元、细胞凋亡和突触后的标志物)表达,以及谷氨酸(Glu)/γ-氨基丁酸(GABA)平衡的丧失,海马中异常的 GAD67(Gad1)表达。氯氮平部分改善了一些类似SCZ的行为,逆转了Glu/GABA比例失调,并恢复了cKO小鼠中GAD67的表达:结论:Zfp804a cKO小鼠重现SCZ样病理和行为表型的研究获得成功。结论:Zfp804a cKO小鼠成功重现了SCZ样病理和行为表型,并确定了一种新的机制,即Zfp804a导致Glu/GABA失衡和GAD67表达减少,而氯氮平治疗可部分恢复这一机制。这些发现强调了基因表达改变在理解SCZ发病机制中的作用,并为未来的治疗干预和生物标记物发现提供了一个可靠的SCZ模型。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Schizophrenia-Like Deficits and Impaired Glutamate/Gamma-aminobutyric acid Homeostasis in Zfp804a Conditional Knockout Mice.

Background and hypothesis: Zinc finger protein 804A (ZNF804A) was the first genome-wide associated susceptibility gene for schizophrenia (SCZ) and played an essential role in the pathophysiology of SCZ by influencing neurodevelopment regulation, neurite outgrowth, synaptic plasticity, and RNA translational control; however, the exact molecular mechanism remains unclear.

Study design: A nervous-system-specific Zfp804a (ZNF804A murine gene) conditional knockout (cKO) mouse model was generated using clustered regularly interspaced short palindromic repeat/Cas9 technology and the Cre/loxP method.

Results: Multiple and complex SCZ-like behaviors, such as anxiety, depression, and impaired cognition, were observed in Zfp804a cKO mice. Molecular biological methods and targeted metabolomics assay validated that Zfp804a cKO mice displayed altered SATB2 (a cortical superficial neuron marker) expression in the cortex; aberrant NeuN, cleaved caspase 3, and DLG4 (markers of mature neurons, apoptosis, and postsynapse, respectively) expressions in the hippocampus and a loss of glutamate (Glu)/γ-aminobutyric acid (GABA) homeostasis with abnormal GAD67 (Gad1) expression in the hippocampus. Clozapine partly ameliorated some SCZ-like behaviors, reversed the disequilibrium of the Glu/GABA ratio, and recovered the expression of GAD67 in cKO mice.

Conclusions: Zfp804a cKO mice reproducing SCZ-like pathological and behavioral phenotypes were successfully developed. A novel mechanism was determined in which Zfp804a caused Glu/GABA imbalance and reduced GAD67 expression, which was partly recovered by clozapine treatment. These findings underscore the role of altered gene expression in understanding the pathogenesis of SCZ and provide a reliable SCZ model for future therapeutic interventions and biomarker discovery.

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来源期刊
Schizophrenia Bulletin
Schizophrenia Bulletin 医学-精神病学
CiteScore
11.40
自引率
6.10%
发文量
163
审稿时长
4-8 weeks
期刊介绍: Schizophrenia Bulletin seeks to review recent developments and empirically based hypotheses regarding the etiology and treatment of schizophrenia. We view the field as broad and deep, and will publish new knowledge ranging from the molecular basis to social and cultural factors. We will give new emphasis to translational reports which simultaneously highlight basic neurobiological mechanisms and clinical manifestations. Some of the Bulletin content is invited as special features or manuscripts organized as a theme by special guest editors. Most pages of the Bulletin are devoted to unsolicited manuscripts of high quality that report original data or where we can provide a special venue for a major study or workshop report. Supplement issues are sometimes provided for manuscripts reporting from a recent conference.
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