Disorder Of GABAergic System And Behavior In Offspring Rats With Prenatal Infection

BackgroundSchizophrenia is a group of serious mental diseases with unknown etiology and prolonged course of disease.Epidemiological data show that infection during pregnancy is an important risk factor for schizophrenia.Maternal immune activation induced by Poly I:C showed schizophrenia-like behavior in offspring rats and abnormalities in GABAergic inhibitory neurotransmitters in the brain of offspring rats.However,it is not clear about its underlying molecular mechanism.ObjectiveIn this study,infection during pregnancy rat model was constructed the expression of GABAergic-related molecular in different neurodevelopmental stages of offspring were analyzed to investigate the effects of infection during pregnancy on behavior and GABAergic system of offspring.MethodsRats were injected with Poly I: C at a dose of 10 mg/kg on the 9th day of pregnancy to prepare a pregnant infection model.The behavior tests of MIA offspring were carried on adolescence and adulthood respectively.The concentration of GABA in CSF of adult Poly I:C group was detected by High Performance Liquid Chromatography.Quantitative Real-time PCR and Western blotting were used to detect GABAergic-related RNA and protein changes in hippocampus and frontal lobe.The expression and distribution of GAD67,VGAT and GAT1 in hippocampus were detected by immunofluorescence technique.First order partial correlation statistical method was used to analyze the correlation between GABA expression level and behavior of presynaptic proteins in different developmental stages.Results 1.Inflammatory cytokines levels in pregnant rats treated with Poly I: C were higher than those in saline group.2.No obvious difference in behavioral test was found between MIA offspring and control group at adolescence.Whereas,the adult offspring of MIA group showed increased anxiety,impaired memory and PPI deficit.In the open field test,the distance moved in central area was decreased significantly for adult MIA offspring.In the elevated cross maze test,the frequency and time of entry into the open arms were reduced in adult MIA offspring.In the Y maze test,the frequency and time of entry into the novel arm were decreased in adult Poly I:C group;In Prepulse inhibition(PPI)test,the inhibition rate was significantly reduced in the adult MIA offspring.3.The results of RT-PCR showed that the mRNA levels of GABA transporter protein VGAT and GAT1 in the frontal lobe of adult rats was significantly higher in Poly I:C group than those in saline group.However,there was no change in other detection molecules in the hippocampus and frontal lobes during the lactation,puberty and adulthood.4.Compared with NaCl group,GAT1 protein levels in the hippocampus of Poly I:C group were decreased during puberty and increased in adulthood,and increased in the frontal lobe during puberty;VGAT protein decreased in the hippocampus during lactation and adolescence,but no significant change was found in the prefrontal lobe;NKCC1 protein levels decreased in the hippocampus and prefrontal cortex during weaning and adolescence,and increased in the hippocampus and prefrontal cortex during adulthood;KCC2 protein levels in the hippocampus were increased during weaning and adolescence,but decreased during adulthood.Besides,KCC2 protein levels were increased in the in prefrontal cortex during adulthood.5.Compared with NaCl group,the fluorescence density value VGAT in the hippocampus of Poly I:C group was decreased in the hippocampus during lactation,and was increased during adolescence;The fluorescence density value of GAT1 in the hippocampus of Poly I:C group was decreased during adolescence and adulthood.6.The results of correlation analysis showed that the protein level of GAT1 was positively correlated with the distance of open field center area,the number of times of entering open arm in elevated cross maze and PPI in hippocampus of adult offspring rats of MIA,and the protein level of KCC2 was positively correlated with the time of entering new arm in Y maze and PPI,while the protein level in frontal lobe prefrontal NKCC1 was negatively correlated with PPI.ConclusionsThere were obvious schizophrenia-like behaviors in the offspring of MIA,and the expression of multiple molecular related to GABAergic system was abnormal in both hippocampus and frontal lobe.GABAergic system disorders occured earlier than behavioral abnormalities,which suggested its role in the early stages of disease.Thus,our study provides a new direction for the prevention and treatment of schizophrenia.