ZFP804A mutant mice display sex-dependent schizophrenia-like behaviors

Ying Huang,Ning-Ning Song,Yun-Qing Hu,Qi-Xin Zhou,Sheng-Xi Wu,Yu-Qiang Ding,Jing Huang,Ling Hu,Chun-Xian Yang,Wan-Ying Mei,Lei Zhang,Qiong Zhang,Lin Xu,Cui-Ping Yang

doi:10.1038/s41380-020-00972-4

Abstract

Genome-wide association studies uncovered the association of ZNF804A (Zinc-finger protein 804A) with schizophrenia (SZ). In vitro data have indicated that ZNF804A might exert its biological roles by regulating spine and neurite morphogenesis. However, no in vivo data are available for the role of ZNF804A in psychiatric disorders in general, SZ in particular. We generated ZFP804A mutant mice, and they showed deficits in contextual fear and spatial memory. We also observed the sensorimotor gating impairment, as revealed by the prepulse inhibition test, but only in female ZFP804A mutant mice from the age of 6 months. Notably, the PPI difference between the female mutant and control mice was no longer existed with the administration of Clozapine or after the ovariectomy. Hippocampal long-term potentiation was normal in both genders of the mutant mice. Long-term depression was absent in male mutants, but facilitated in the female mutants. Protein levels of hippocampal serotonin-6 receptor and GABAB1 receptor were increased, while those of cortical dopamine 2 receptor were decreased in the female mutants with no obvious changes in the male mutants. Moreover, the spine density was reduced in the cerebral cortex and hippocampus of the mutant mice. Knockdown of ZFP804A impaired the neurite morphogenesis of cortical and hippocampal neurons, while its overexpression enhanced neurite morphogenesis only in the cortical neurons in vitro. Our data collectively support the idea that ZFP804A/ZNF804A plays important roles in the cognitive functions and sensorimotor gating, and its dysfunction may contribute to SZ, particularly in the female patients.

Highlights

Schizophrenia (SZ) is a debilitating mental disorder with a lifetime prevalence rate of about 1% [1]
Imaging genetics studies have demonstrated that healthy carriers of rs1344706 risk allele exhibit strong gene dosage-dependent changes in the functional coupling of the dorsolateral prefrontal cortex across the hemispheres and hippocampus, the observation which parallels the similar findings in SZ patients [14, 19]
ZNF804A rs1344706 may be associated with deficits in episodic and working memory [20,21,22], as well as in the cognitive function according to the data from combining polygenic scores with the risk variants in SZ patients [23]

Summary

Introduction

Schizophrenia (SZ) is a debilitating mental disorder with a lifetime prevalence rate of about 1% [1]. Imaging genetics studies have demonstrated that healthy carriers of rs1344706 (an intronic SNP site in ZNF804A) risk allele exhibit strong gene dosage-dependent changes in the functional coupling of the dorsolateral prefrontal cortex across the hemispheres and hippocampus, the observation which parallels the similar findings in SZ patients [14, 19]. Male SZ patients tend to show more severe symptoms, worse cognitive function, poorer treatment response, and generally worse prognosis than female SZ patients do [29, 30] These sex differences are evident in the core symptoms: female SZ patients have more affective symptoms while the male patients have more negative symptoms [29,30,31]. Our results provide new insight into the role of ZFP804A and, by implication, human ZNP804A in cognition and sensorimotor gating, relevant to the core symptoms of SZ

Materials and methods

Results

Discussion

Findings

Compliance with ethical standards