| BackgroundMaternal immune activation during first trimester is considered to increase the risk of disease in the offspring,including schizophrenia and autism.Abnormalities in the offspring,such as neuropathological changes and behavioral disorders,may be due to maternal immune activation leading to the abnormal brain development in the fetus.Many studies have focused on the role of Reelin in the etiology and pathology of schizophrenia.Reelin,an extracellular matrix protein,can mediate the correct positioning of neurons,guide the formation of cortical lamellar structure,and regulate the function and plasticity of synapses during development.However,there is no systematic study between the important developmental stages of maternal immune activation of offspring and Reelin and its signaling pathway molecules,and thus further exploration is needed.ObjectivesIn this study,maternal infection model in early pregnancy was used to study the expression changes of RELN and its downstream signaling pathway molecules,synaptic development characteristics and behavioral changes in the important developmental stages of offspring,and to explore whether RELN and its signaling pathway are involved in maternal infection mediated neurodevelopmental disorders in offspring.MethodsOn the 9th day of pregnancy,Sprague-Dawley rats were injected with a dose of 10mg/kg Poly I: C(model group)or equal volume of 0.9% saline(control group)through the tail vein.After 3 hours of injection,the levels of inflammatory factors IL-1β,IL-6 and TNF-α in the plasma of pregnant rats were detected to evaluate the success of maternal immune activation model.Behavioral evaluation was performed using open field,Y maze and elevated plus maze tests and prepulse inhibition of the auditory startle reflex to assess schizophrenic behavior in adult rat.Meanwhile,The number and morphology of dendritic spines were detected by Golgi staining in adult rats.In addition,western blotting,immunofluorescence and q-PCR were used to detect the expression of Reelin and its downstream signaling pathway in the hippocampus and frontal lobe of offspring at various developmental stages.SPSS 22.0 was used for statistical analysis.Results1 The expression levels of inflammatory factors IL-1β,IL-6 and TNF-α in the plasma of the model group were significantly higher than those of the control group,which proved that the maternal immune activation model was successfully prepared.2.In the open field experiment,the distance traveled in the central area and the distance traveled in the center of the rats as a percentage of the total distance decreased significantly in model group.The duration of stay in the central area was also significantly reduced in model group.In the elevated plus maze experiment,the time to enter the open arm in the model group was significantly less compared with the control group.In Y maze experiment,the time to enter the new arm in the model group was significantly less.In the prepulse inhibition experiment,the inhibition rates of the model group were significantly reduced at75 d B,80 d B and 85 d B.3.Compared with the control group,the expression level of Reelin protein in the model group was significantly lower in the neonatal hippocampus and prefrontal cortex;the expression level of p-Dab1 protein in the model group was significantly lower in the neonatal hippocampus,and the expression levels of PSD95 and SYN protein in the model group decreased significantly in the hippocampus and frontal lobe respectively during the newborn period.However,Reelin was significantly increased in the hippocampus during the perinatal period in the model group.4.The m RNA of RELN gene level of the model group in the neonatal hippocampus and frontal lobe tissues was significantly lower than that of the control group.5.Immunofluorescence showed that during the embryonic stage,the number of Reelin positive cells in the cortical marginal zone and the hippocampal dentate gyrus decreased,but lamellar arrangement were normal in the two groups.In the neonatal period,the number of Reelin positive cells in the hippocampal dentate gyrus decreased.The dendritic spine density of hippocampal neurons in the model group is lower than that of control group in the Golgi staining experiment.Conclusion1.Infection of Poly I: C in early pregnancy resulted in abnormal expression of progeny Reelin and its downstream molecules,which was spatiotemporal and region-specific.2.Maternal immune activation in early pregnancy can lead to synaptic dysplasia and behavioral disorders in adult offspring,and these disorders lag the occurrence of Reelin abnormalities,suggesting that the abnormal expression of Reelin and its downstream signaling pathway may be the molecular mechanism of synaptic dysfunction and abnormal behavior in offspring caused by maternal immune activation. |
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