Postnatal neurodevelopmental expression and glutamate-dependent regulation of the ZNF804A rodent homologue

Abstract

The zinc finger protein ZNF804A rs1344706 variant is a replicated genome-wide significant risk variant for schizophrenia and bipolar disorder. While its association with altered brain structure and cognition in patients and healthy risk allele carriers is well documented, the characteristics and function of the gene in the brain remains poorly understood. Here, we used in situ hybridization to determine mRNA expression levels of the ZNF804A rodent homologue, Zfp804a, across multiple postnatal neurodevelopmental timepoints in the rat brain. We found changes in Zfp804a expression in the rat hippocampus, frontal cortex, and thalamus across postnatal neurodevelopment. Zfp804a mRNA peaked at postnatal day (P) 21 in hippocampal CA1 and DG regions, and was highest in the lower cortical layers of frontal cortex at P1, possibly highlighting a role in developmental migration. Using immunofluorescence, we found that ZFP804A co-localized with neurons and not astrocytes. In primary cultured cortical neurons, we found that Zfp804a expression was significantly increased when neurons were exposed to glutamate [20 μM], but this increase was blocked by the N-methyl-D-aspartate receptor (NMDAR) antagonist MK-801. Expression of Comt, Pde4b, and Drd2, genes previously shown to be regulated by ZNF804A overexpression, were also significantly changed in an NMDA-dependent manner. Our results describe, for the first time, the unique postnatal neurodevelopmental expression of Zfp804a in the rodent brain and demonstrate that glutamate potentially plays an important role in the regulation of this psychiatric susceptibility gene. These are critical steps towards understanding the biological function of ZNF804A in the mammalian brain.

Interactome analysis reveals ZNF804A, a schizophrenia risk gene, as a novel component of protein translational machinery critical for embryonic neurodevelopment

“…We found that ZFP804A is highly expressed in embryonic brain where it regulates NPC proliferation and neuronal migration. Our results are consistent with recent two studies, 24 , 56 supporting a critical role of ZFP804A in early brain development. Suppression of ZFP804A expression decreased NPC proliferation and migration of cortical neurons, suggesting that the proper expression of ZNF804A is critical for neural development, and that the disrupted expression may lead to disorders.…”

ZFP804A mutant mice display sex-dependent schizophrenia-like behaviors

“…Previous studies have reported that ZFP804A/ZNF804A is widely expressed in rat and human brain, primarily to neurons [4][5][6]. Consistent with these reports, our results show that ZFP804A mRNA is abundantly distributed in the cerebral cortex and hippocampus of adult mice, particularly in layers II/III and V of the cerebral cortex.…”

“…ZNF804A belongs to the zinc-finger protein family containing a C2H2-type domain and is expressed in the brain [3][4][5][6]. Genome-wide association studies (GWAS) have revealed ZNF804A as one of the strongest candidate genes for SZ [4,7,8].…”

A promoter variant in ZNF804A decreasing its expression increases the risk of autism spectrum disorder in the Han Chinese population

“…The role of NLGN4 in ASD has been widely investigated using genetic, neurodevelopmental and biochemical methods 34 . The temporal and spatial expression characteristics of ZNF804A suggest that it is involved in brain development 35 . The regulation of ZNF804A in a series of genes including NLGN4 , may be an important molecular mechanism for ASD.…”