Gene Expression And Promoter Methylation Of GABA Signaling Pathway In SZ And Antipsychotics Treatment

Objective Deficits in the γ-aminobutyric acid（GABA）system have been reported to play an important role in schizophrenia（SZ）of postmortem studies.Recent studies suggest that alterations of GABA signaling pathway related genes mRNA expression and DNA methylation are associated with SZ.In our study,GABA signaling pathway related genes mRNA expression and promoter methylation of GABRB2 gene in peripheral blood mononuclear cell（PBMC）were investigated to explore the machanisms involved in SZ and antipsychotics treatment.Methods Total RNA isolated from PBMC samples of 53 SZ patients and 53 gender/age matched healthy controls.12 out of 53 SZ patients were followed 8 weeks antipsychotic treatment.Expression of GABRB2,and the epigenetic regulatory enzymes ten-eleven translocation-1（TET1）and DNA methyltransferases（DNMTs）in PBMC was analyzed using SYBR Green real-time PCR.The quantitative GABRB2 promoter methylation was analyzed using the high-throughput mass spectrometry on matrix-assisted laser desorption/ionization time-of-flight（MALDI-TOF）mass array.Results 1.Results showed that no significantly differences in the expression of DNMT1、GABRB2 and TET1 between control and case group（P>0.05）,but DNMT3 a mRNA expression significantly increased in SZ patients compared to healthy controls（P=0.012）,and the difference was observed specially in males（P=0.002）but not in females（P>0.05）.In SZ patients followed 8 weeks antipsychotics treatment,no significant mRNA expression differences for these four genes was detected between pre-treatment and after-treatment（P>0.05）.2.No significant differences between the GABRB2 promoter methylation pattern of control and case group was detected（P>0.05）.However,significant differences in the methylation levels of CpG₂8 in the GABRB2 promoter were found in males（P=0.033）.In SZ patients followed 8 weeks antipsychotics treatment,we detected a significant increase of GABRB2 promoter methylatin after treatment（p=0.000）.3.Spearman correlation analysis did not show any significant correlation between GABRB2 promoter methylation pattern and GABA signaling pathway related genes（DNMT1、DNMT3a、TET1 and GABRB2）mRNA expression（P>0.05）,and also no significant correlation was detected between the levels of a specific CpG（CpG₂8）in GABRB2 promoter and DNMT3 a gene expression（P>0.05）.Conclusions 1.An upregulation of DNMT3 a mRNA expression in PBMC of SZ patients suggested an alteration of DNA methylation in peripheral blood of SZ patients.2.A downregulation of GABRB2 promoter methylation in PBMC of SZ patients after-treatment supported that GABRB2 promoter methylation in PBMC may associated with the machanisms of antipsychotics treatment in SZ.