运动对孤独症谱系障碍大鼠内侧前额叶皮层树突棘重塑的影响及MARK1/MAP1A/PSD-95通路的作用OA北大核心CSTPCD

AIM:To investigate the effects of exercise training(swimming combined with wheel running)on dendritic spine remodeling in the medial prefrontal cortex of rats with autism spectrum disorder(ASD)induced by valproic acid(VPA),and to explore the roles of microtubule affinity regulating kinase 1(MARK1),microtubule-associated pro-tein 1A(MAP1A)and postsynaptic density protein-95(PSD-95).METHODS:The ASD model rats and normal control rats were generated by collecting the male offspring of rats exposed to VPA or normal saline during pregnancy.The rats were randomly divided into an exercise group and a sedentary group,with 9 to 11 rats in each group.The effect of exercise on the sociability of the rats with ASD was evaluated by a social behavior test.The density and morphology of dendritic spines in the prelimbic cortex(PrL)and infralimbic cortex(IL)were observed following stereotaxic injection of a fluores-cent virus.Western blot was used to assess the protein expression of PSD-95 and synaptophysin(Syn),and RNA in situ hybridization was used to determine the RNA expression and colocalization of MARK1,MAP1A and PSD-95.RE-SULTS:The time spent in the chamber containing an unfamiliar rat and the time and frequency of sniffing the unfamiliar rat were significantly lower in the ASD model group than that in the control group,demonstrating that the sociability of the ASD model rats was impaired(P<0.05).After exercise intervention,the social behavior of the ASD model rats signifi-cantly improved(P<0.05).The total spine density,mushroom spine density,and stubby spine density were significantly increased in the PrL but not in the IL of the ASD model rats,and these changes were effectively reversed after exercise in-tervention.Western blot analysis showed that exercise intervention effectively abrogated the increase in the protein expres-sion of PSD-95 in the PrL of the ASD model rats(P<0.05).However,the expression of Syn in the PrL and the expression of PSD-95 and Syn in the IL were not significantly different.RNA in situ hybridization experiments showed that exercise in-tervention effectively reduced the number of RNA-positive particles of MARK1,MAP1A and PSD-95 in the PrL of the ASD model rats and reduced the colocalization of MARK1 and MAP1A,MARK1 and PSD-95 and MAP1A and PSD-95.CONCLUSION:Exercise intervention may improve the remodeling of dendritic spines through MARK1/MAP1A/PSD-95 signaling in the PrL,thereby improving the social behavior of ASD model rats.