PDLIM5 Improves Depression-like Behavior And Methylation Of PDLIM5 Promoter Has Sex Differences In Prenatal Stress

Objective: Prenatal stress(PS)contributes to depressive-like behavior in the offspring.PDLIM5 is involved in the onset of mental disorders.This study was to investigate the role and mechanism of PDLIM5 in depressive-like behavior of PS offspring rats.Methods: The 60-day-old SD rats(female 230-250 g,male 280-350g)were used in this experiment.They were caged at 20:30 every night in a ratio of male to female 3:1.The female rats were examined by vaginal smear before 8:00 am next day.Pregnant female rats were randomly divided into two groups: Control group(CON)and PS group.In the third trimester,just 7 days before Labor for restraint stress.On the 21 st day after delivery,the pups were separated from their matern and caged according to their sex.The offspring were divided into the following groups: CON group,PS group,PS+normal saline group(PS+NS),PS+PDLIM5 group,PS+PDLIM5 sh RNA group,PS+ 5-aza D group.The rats were injected with the same amount of PDLIM5,normal saline,PDLIM5 sh RNA or PS+5-aza D in both hippocampal areas every day for three consecutive days.Seven days after surgery,the depressive-like behaviors were assessed by sucrose preference test(SPT)and forced swimming test(FST).m RNA and protein expression levels of PDLIM5 in hippocampus of offspring rats were detected by q RT-PCR and Western Blot.In addition,the methylation of PDLIM5 gene promoter region was detected by immunohistochemistry,and its sulfite sequencing was performed.Results:1.In the SPT,the percentage of sugar water preference in the PS group was significantly reduced compared with the CON group;In the FST,the immobility time of the PS group was significantly prolonged,while the results of intraperitoneal injection of 5-aza D in the offspring of PS group showed that 5-aza D could reverse the depressive-like behavior in the offspring of PS group,and there was no significant difference between male and female offspring(p>0.05).2.The results of Western Blot and q RT-PCR showed that the expression of PDLIM5 m RNA and protein in the hippocampus of PS male rats was significantly lower than that of CON group,while the expression of PDLIM5 m RNA and protein in female group was unchanged,indicating that there was gender difference between male and female offspring(p<0.05).3.The results of sulfite sequencing showed that the DNA methylation level of PDLIM5 promoter in the hippocampus of PS male rats increased significantly,while that of PDLIM5 promoter in the hippocampus of female rats did not change,indicating that there was gender difference between male and female offspring.(p<0.05).Conclusion: PDLIM5 can significantly improve the depressive-like behavior of both male and female PS offspring rats,while the PDLIM5 promoter methylation is only observed in male PS offspring rats.Our study may provide new mechanism for the pathogenesis of depression and experimental evidence for sex-based precise treatment.