Study On Neuroimmune System Changes And Pathogenic Mechanism In Two Kinds Of Exposures-induced Autism Spectrum Disorder Model With Wistar Rat

Objective To establish two kinds of exposures-induced autism models in Wistar rat, study the changes of neuroimmune system in exposed rat and offspring, and discuss whether the maternal cytokines skewing can cause the changes of neuroimmune system in offspring and the pathogenic mechanism.Methods 12 week-old rats are randomly divided into three groups of each 10. The rat valproate-induced autism model is injected intraperitoneally with 600mg/kg VPA at gestational day 12.5, while the rat LPS-induced autism model is injected intraperitoneally with 25mg/kg LPS at gestational day 11.5. Detect the level of IL-1β, IL-4, IL-6, IL-10, IFN-γ, TGF-β in mother and offsprings. Observe the histopathological damage in brain with enzyme-linked immuno sorbent assay and immunohistochemical staining. Evaluate rat antism-like social behavior through the social interaction test.Results Contrast with the normal control group, the level of IL1-β, IL-6, IL-10, IFN-γ, TGF-β skew in two kinds of exposures-induced autism models, with statistically significant(P<0.05), except for IL-4. In both maternal exposure groups, the level of IL-4, IFN-γ elevate, while IL-10 only increased in LPS exposure group and IL1-β, IL-6 and TGF-β only changed in VPA exposure group. Pathology results of two model groups show that there is no change in cerebral cortex but exist bits of telangiectatic vessels in the brain.No inflammatory cell infiltrate in the stroma. The positive degree of proliferative microglia and astrocyte is higher than the control group. The results of social interaction test illustrate the model rats have less social interaction behavior than the controls, with statistically significant(P<0.05). In VPA induced ASD group, the results of social interaction,’the approach-avoidance score’, is inversely correlated with the level of IL1-β, IL-4 and IL-10( r=-0.802、-0.781,-0.766, P<0.05), while in LPS induced ASD group, the results of social interaction,’the approach-avoidance score’, is positively correlated with the level of IFN-γ( r=0.756,P<0.05).Conclusion Both two model groups rats exist immune activation persistent, which lead the the model rats have less social interaction behavior than the controls. The dysfunction of immune system is one of the most important cause of ASD. In exposure of VPA, during the first trimester,may active maternal immune system, which can elevate maternal pro-inflammatory cytokines and disturb the immune homeostasis. Elevated pro-inflammatory cytokines pass through the placenta, enter the fetal circulation, cross the fetal blood-brain barrier,cause aberrant fetal neuronal growth and plasticity and ultimately cause ASD in offspring.