The Role Of RhoA And Intervention Of Simvastatin In Depression-like Behavior Of Prenatal Stress Offspring Rats

Objective: As a common disease,depression is usually characterized by persistent low mood,lack of motivation,depression,and can lead to suicide in the most severe cases.Prenatal stress exposure can cause depressive behavior in rodent offspring,but the underlying mechanism remains unclear.RhoA(Ras homolog gene family,member A)plays an important role in stress-related changes in synaptic plasticity,and is involved in the occurrence of depression through activation of ROCK,a downstream effector molecule(Rho-associated protein kinase),to initiate downstream pathways.In present study,a PS model was established to investigate the changes of RhoA and ROCK1/2 gene expression levels in depressive behavior in PS offspring.We also injected Simvastatin,a RhoA inhibitor,to observe the effect of depression in PS offspring.Methods:The animal model used in present study was prenatal restraint stress model.PS female rats were subjected to restraint stress(3 times per day,45 min per time)during 14-20 d of pregnancy,while female rats in the control group were not disturbed during pregnancy.The rats were divided into control group(CON,n=8),prenatal stress group(PS,n=8),prenatal stress + normal Saline group(PS-Saline,n=8),and prenatal stress + simvastatin group(PS-SMV,n=8)on the 21 st day of birth.Simvastatin was injected intraperitoneally in PS-SMV group from 44 d to 50 d after birth for 7 consecutive days.Sucrose preference test,forced swimming test,and open field test were performed on days 51,52,and 53,respectively,to assess depressive behavior.Finally,western blotting and RT-q RCR were used to determine changes in the expression of RhoA,ROCK1 and ROCK2 protein and m RNA in hippocampus and prefrontal cortex.Results:1.The percentage of sucrose preference in PS group was significantly decreased than that in control group.The immobility time of forced swimming was significantly prolonged than that of the control group.In the open field test,the number of the total crossing,the times of crossing the central grid and the time spent in the center were significantly reduced,that is,they showed obvious depression-like behavior.2.The results of RT-q PCR and Western-blotting showed that PS significantly increased RhoA m RNA and protein expression levels in the hippocampus and prefrontal cortex,and meanwhile increased ROCK1 and ROCK2 m RNA and protein expression levels.3.Intraperitoneal injection of simvastatin can increase the percentage of sucrose preference,reduce the time of forced swimming immobility,improve the motor activity of offspring in open field test and have a certain relieving effect on depression-like behavior.In addition,simvastatin significantly down-regulated the m RNA and protein expressions of RhoA and ROCK2 in the hippocampus and prefrontal cortex,but had no effect on the expression of ROCK1.Conclusions:PS can lead to depression-like behavior in offspring rats,which maybe caused by the up-regulate of RhoA expression and may also be related to the increased expression levels of ROCK1 and ROCK2.After the administration of simvastatin in PS offspring,with the reduction of RhoA and ROCK2 expression levels,the depression-like behavior of PS offspring was significantly improved,further indicating that RhoA may be involved in the occurrence of PS-induced depression-like behavior in offspring and may serve as a potential target for antidepressant treatment.