Abstract
A single nucleotide polymorphism in the ZNF804A gene, rs1344706, is associated with schizophrenia. The polymorphism has been suggested to alter fetal expression of ZNF804A. It has also been reported to be associated with altered cortical functioning and neural connectivity in the brain. Since developmental mechanisms are suggested in the pathophysiology for schizophrenia, expression of Zfp804A, the rat homolog of ZNF804A, was investigated in the developing rat brain. We found that expression of Zfp804A in most brain regions is developmentally regulated and peaks around birth, where after it decreases towards adult levels. This time point is developmentally the equivalent to the second trimester of fetal development in humans. An exception to this expression pattern is the hippocampus where the expression of Zfp804A appears to increase again in the adult brain. Using laser capture and quantitative PCR we found that Zfp804A mRNA expression in the adult rat hippocampus is highest in the CA1 sub region, where the overall firing rates of neurons is higher than in the CA3 region. In cultured cortical neurons Zfp804A mRNA expression peaked at day 4 and then decreased. The ZFP804A protein expression was therefore investigated with immunochemistry in such cultures. Interestingly, before day 4, the protein is mostly found in the perinuclear region of the cell but at day 4, ZFP804A was instead found throughout the cell and particularly in the growth cones. In conclusion we demonstrate that Zfp804A increases in the rat brain at the time of birth, coinciding with neuronal differentiation. We also show that ZFP804A is localized to growth cones of growing neurites. These data implicate ZFP804A in growth cone function and neurite elongation. The polymorphism rs1344706 lowers expression of ZNF804A during prenatal brain development. This may affect ZNF804A’s role in cone function and neurite elongation leading to synaptic deficits and altered neural connectivity.
Highlights
Schizophrenia is a severe psychiatric disorder characterized by delusions, hallucinations, altered cognition, emotional reactivity and disorganized behaviour [1]
The mRNA levels dropped again at postnatal day 5 (P5) in the frontal cortex and P3 in cerebellum (Fig 1A and 1B) to levels similar to those found in adult brain
This pattern was not seen in the brainstem or the spinal cord where ZFP804A was stably expressed at low levels at the same time points
Summary
Schizophrenia is a severe psychiatric disorder characterized by delusions, hallucinations, altered cognition, emotional reactivity and disorganized behaviour [1]. ZNF804A was the first gene to achieve genome-wide significance for psychosis [1], and several studies have confirmed an association between schizophrenia and a single nucleotide polymorphism, rs1344706, in the ZNF804A gene [5,6,7,8,9] This polymorphism is associated with altered expression of the gene in the dorsolateral prefrontal cortex in fetal [10, 11] but not adult brain [10,11,12]. A new human transcript was identified in the brain [10] This isoform lacks the first 135 amino acids of ZNF804A, which includes the zinc-finger domain suggesting another function than a role in transcription. These data further implicate ZNF804A in development and neurite outgrowth
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