Schizophrenia-Like Deficits and Impaired Glutamate/Gamma-aminobutyric acid Homeostasis in Zfp804a Conditional Knockout Mice

条件基因敲除 加巴能 海马体 生物 神经科学 谷氨酸受体 γ-氨基丁酸 谷氨酸脱羧酶 精神分裂症(面向对象编程) 心理学 表型 遗传学 生物化学 基因 受体 精神科 抑制性突触后电位
作者
Qiao-xia Zhang,Shanshan Wu,Pengjie Wang,Rui Zhang,Robert K. Valenzuela,Shan-shan Shang,Ting Wan,Jie Ma
出处
期刊:Schizophrenia Bulletin [Oxford University Press]
标识
DOI:10.1093/schbul/sbae120
摘要

Abstract 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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