Schizophrenia is a serious mental disorder that affects up to 2% of the global population. Males are typically affected earlier, with onset in late adolescence or early adulthood, and more severely than females. Symptoms of schizophrenia are divided into three categories: Positive symptoms, negative symptoms, and cognitive symptoms. Schizophrenia is mainly treated with antipsychotics, which can be categorized as first-generation antipsychotics (FGAs) or second-generation antipsychotics (SGAs). The side-effects from FGAs include extrapyramidal symptoms, and due to these side-effects, SGAs are often preferred, as they have a milder side-effect profile.
Despite intense research, the etiology and pathophysiology of schizophrenia still remains unclear. However, it is generally accepted that schizophrenia is a multifactorial neurodevelopmental disorder influenced by genetic, epigenetic, and environmental factors. Suggested correlations between epigenetics and environmental factors include place and time of birth, parasitic infections, low IQ, maternal nutrition, and obstetric complication.
DNA methylation, gene expression, and histone modification are thought to play a role in the development of schizophrenia. Genes suggested to be involved in the pathophysiology of schizophrenia include activity-regulated cytoskeleton-associated protein (Arc), cfos, and brain-derived neurotrophic factor (BDNF).
The aims of this study were to (1) evaluate the effect of acute phencyclidine (PCP) administration (10 mg/kg) in a time study on mRNA expression of three schizophrenia-susceptible genes: Arc, cfos, and BDNF, in the PFC of adult rats, (2) evaluate the level of H4 acetylation of the promoters in rat PFC, following acute PCP administration, corresponding to each of the mRNA being investigated, (3) evaluate the level of H3 phospho-acetylation of the promoters in rat PFC, following acute PCP administration, corresponding to each of the mRNA being investigated , and (4) evaluate if a correlation between PCP-induced mRNA expression in Arc, cfos, and BDNF, and the H4 acetylation and H3 phospho-acetylation in their corresponding promoters, exist.
Gene expression analysis and chromatin immunoprecipitation (ChIP) assay was performed on prefrontal cortex (PFC) from 30 young adult, male Sprague-Dawley rats. The rats were divided into seven groups: Two control groups and five experimental groups, with acute administration of PCP in the experimental groups. Primers were designed based on mRNA sequences of Arc, cfos, and BDNF, and quantitative RT-PCR was performed in order to evaluate the PCP-induced mRNA expression of Arc, cfos, and BDNF in a time dependent manner. mRNA expression of Arc, cfos, and BDNF was evaluated 60, 120, 240, and 360 minutes as well as 24 hours after PCP administration. β-actin was used as housekeeping gene. Variations in histone H4 acetylation and histone H3 phospho-acetylation were examined on isolated chromatin.
Compared to the control groups, mRNA expression of Arc was significantly increased 240 minutes after PCP administration. Furthermore, mRNA expression of cfos was significantly increased 60 and 120 minutes after PCP administration compared to controls, while the mRNA expression of BDNF was significantly increased 240 and 360 minutes after PCP administration compared to controls. There was an increase in H4 acetylation of cfos and BDNF promoter 360 minutes after administration compared to controls. No differences in H3 phospho-acetylation of Arc, cfos, or BDNF was found when compared to controls.
In conclusion, acute administration of PCP in rat significantly increased the mRNA expression of Arc, cfos, and BDNF in the rat PFC, however at different time points. Increased H4 acetylation of cfos and BDNF promoter was also observed following PCP administration. This finding in BDNF mRNA correlated with the level of H4 acetylation of the corresponding BDNF promoter I, which also peaked in the PCP 360 min group. Thus, acute PCP administration might induce H4 acetylation in the BDNF promoter I, leading to an increase in BDNF mRNA expression, suggesting a transcriptional regulation of BDNF.