DNA methylation regulates gabrb2mRNA expression: developmental variations and disruptions in l‐methionine‐induced zebrafish with schizophrenia‐like symptoms

Abstract

Single nucleotide polymorphisms (SNPs) in the human type A gamma-aminobutyric acid (GABA) receptor β subunit gene (GABRB2) have been associated with schizophrenia and quantitatively correlated with mRNA expression in the postmortem brain tissue of patients with schizophrenia. l-Methionine (MET) administration has been reported to cause a recrudescence of psychotic symptoms in patients with schizophrenia, and similar symptoms have been generated in MET-induced mice. In this study, a zebrafish animal model was used to evaluate the relationship between the gabrb2 mRNA expression and its promoter DNA methylation in developmental and MET-induced schizophrenia-like zebrafish. The results indicated developmental increases in global DNA methylation and decreases in gabrb2 promoter methylation in zebrafish. A significant increase in gabrb2 mRNA levels was observed after GABA was synthesized. Additionally, the MET-triggered schizophrenia-like symptoms in adult zebrafish, involving social withdrawal and cognitive dysfunction analyzed with social interaction and T-maze behavioral tests, were accompanied by significantly increased DNA methylation levels in the global genome and the gabrb2 promoter. Furthermore, the significant correlation between gabrb2 mRNA expression and gabrb2 promoter methylation observed in the developmental stages became non-significant in MET-triggered adult zebrafish. These findings demonstrate that gabrb2 mRNA expression is associated with DNA methylation varies by developmental stage and show that these epigenetic association mechanisms are disrupted in MET-triggered adult zebrafish with schizophrenia-like symptoms. In conclusion, these results provide plausible epigenetic evidence of the GABA receptor β subunit involvement in the schizophrenia-like behaviors and demonstrate the potential use of zebrafish models in neuropsychiatric research.

Meta-analyses of genome wide association studies in lines of laying hens divergently selected for feather pecking using imputed sequence level genotypes

“…Although we were not able to confirm the aforementioned genes related to GABAergic signaling, we were able to detect 52 intron variants, among them two insertions, with -log10(p) > 5 on GGA13 (8,084,380 -8,135,739 bp), which affect the GABA-receptor subunit GABRB2 (Additional File 2). For GABRB2 as well strong evidence exists to be a causative gene for schizophrenia [43][44][45][46][47][48][49][50] and it seems to be involved in opioid addiction [51]. Iffland et al [6] found the QTL region on GGA1 also associated with FPD, but we were not able to confirm this in our GWAS based on imputed sequence level genotypes.…”

Şizofrenide Epigenetik Bakış Açısı: DNA Metilasyon Modelleri

“…Another study examining DNA methylation in the human type A gamma-aminobutyric acid (GABA) receptor β2 subunit gene (GABRB2) used zebrafish, one of the model organisms, unlike blood, saliva and postmortem brain samples. It showed developmental increases in global DNA methylation and decreased GABRB2 promoter methylation in zebrafish 59 .…”

A critical review of zebrafish schizophrenia models: Time for validation?

“…Similarly, methionine-induced social withdrawal was found in adult zebrafish, which exhibited a reduced preference for a stimulus group of conspecifics in the shoaling paradigm. Moreover, methionine-treated zebrafish failed to remember the location of the reservoir in the T-maze test but did not express any locomotion changes in the novel tank test (Wang et al, 2016). Locomotor activity in zebrafish has also been disrupted by another amino acid.…”