ZFP804A mutant mice display sex-dependent schizophrenia-like behaviors

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.

Zinc in Cognitive Impairment and Aging

“…Female ZFP804A mutant mice show age-dependent defects in sensorimotor gating. Thinking disorder and distraction occurred only after 6 months of age, while the damage to spatial and fear memory was obvious when they were young [ 201 ]. Researchers also found that the deletion of ZFP804A had an impact on the language, reading, and cognitive abilities of the population.…”

Stratification by Sex and Hormone Level When Contrasting Men and Women in Schizophrenia Trials Will Improve Personalized Treatment

“…This latter point is important because there is evidence from animal studies that estradiol exerts a substantial effect on cognition [ 41 , 42 , 43 , 44 ]. Preclinical studies have shown, for instance, that mutant mice display sex-dependent schizophrenia-like behaviors in animal models [ 45 ]. Male rats in animal models show significantly more severe cognitive dysfunction than female rats [ 46 ].…”

Application of animal experimental models in the research of schizophrenia

“…Following the discovery of this gene, researches using model organisms to examine the biological functions of DISC1 have achieved fruitful results. There are three main types of Disc1 mouse models of schizophrenia: haploinsufficient dose model, point mutation model and transgenic model (Tomoda, Sumitomo, Jaaro‐Peled, & Sawa, 2016), as outlined in Table 3 (Arguello & Gogos, 2010; Babovic et al, 2007; Bhardwaj, Ryan, et al, 2015; Brown et al, 2011; Brzozka & Rossner, 2013; Clapcote et al, 2007; Gandal et al, 2012; Glen Jr. et al, 2014; Guo et al, 2009; Hikida et al, 2007; Huang et al, 2014; Huang et al, 2020; Koike et al, 2006; Kuroda et al, 2011; Lee et al, 2013; Li, Zhou, et al, 2007; Lipina et al, 2010; Olaya et al, 2018; Ortega‐Alvaro et al, 2011; Papaleo et al, 2016; Pei et al, 2014; Petit et al, 2017; Pletnikov et al, 2008; Shoji et al, 2012; Sobue et al, 2018; Su et al, 2014; Zhang et al, 2015).…”

“…Long‐term depression was only facilitated in female mutant mice. The results suggested that ZNF804A plays an important role in the cognitive functions and sensorimotor gating, particularly in the female patients (Huang et al, 2020).…”