[Enhanced autophagy activates p38/MEF2C pathway to regulate the expression of synapse-associated proteins and improve the symptoms of autistic rats].

: Objective To study the mechanism of p38/myocyte enhancer factor 2C (p38/MEF2C) pathway regulating synapse before and after autophagy intervention in the prefrontal cortex of autistic rats. Methods An animal model of autism was induced by intraperitoneal injection of valproic acid (VPA) at 12.5 days of gestation in Wistar rats. They were treated with normal saline or VPA. The offspring of the saline treatment group served as a control group. The offspring of the VPA treatment group were randomly divided into the model group, 5 mg/kg 3-methyladenine (3-MA) group, and 5 mg/kg rapamycin (Rap) autophagy enhanced group, and the treatment time of each group was from the 35th day of birth to the 42nd day of birth. Western blot analysis was used to detect the protein levels of p38, phosphorylated p38 (p-p38), MEF2C, synaptic vesicle protein (SYN), postsynaptic density 95 (PSD-95), and gephyrin protein in the prefrontal cortex of rats; immunohistochemical staining was used to detect the expression and distribution of SYN, PSD-95 and gephyrin in the prefrontal cortex, and semi-quantitative analysis was performed then. Results Compared with the control group, the developmental and behavioral test showed that the model group had developmental lag and social disorder. Compared with the model group, the Rap group shoed improved social disorder, and the 3-MA group could aggravate social disorder. Compared with the control group, the expression of p38, p-p38, MEF2C was down-regulated, the expression of SYN and PSD-95 protein was up-regulated, and the expression of gephyrin was down-regulated. Compared with the model group, the expression of p38, p-p38, MEF2C in the Rap group was up-regulated, the levels of SYN and PSD-95 protein were down-regulated, and the level of gephyrin protein was up-regulated, while that in 3-MA group was opposite. Compared with the control group, the number of SYN and PSD-95 positive cells in the model group increased, and the number of gephyrin positive cells decreased. Compared with the model group, the number of SYN and PSD-95 positive cells in the Rap group decreased, and the number of gephyrin-positive cells increased, and the 3-MA group was opposite. Conclusion The p38/MEF2C signaling pathway is inhibited in the prefrontal cortex of rats with autism, which can regulate the expression of synaptic related proteins and improve autistic behavior by enhancing autophagy to activate the p38/MEF2C signaling pathway.