关键词: 嘌呤能受体P2X配体门控离子通道7, NOD样受体家族含pyrin结构域蛋白3, 自闭症谱系障碍, 行为学, 线粒体

Abstract: Autism spectrum disorder (ASD) is a severe neurodevelopmental disorder characterized by social deficits and repetitive, stereotyped behaviors. In recent years, its global prevalence has continued to rise, but its pathogenesis remains unclear. Neuroinflammation and mitochondrial dysfunction are considered two key components in the pathological process of ASD, and a vicious cycle may exist between them. However, whether this cycle is driven by the P2X7R/NLRP3 signaling pathway and what specific role it plays in the development of ASD behavioral phenotypes remain to be systematically validated. In this study, a sodium valproate-induced ASD mouse model was used, and the mice were randomly divided into a control group, a model group, and an intervention group treated with the P2X7R-selective antagonist A-438079. Social skills, novelty preferences, and stereotyped behaviors were assessed using the three-box social test, bead embedding test, and self-grooming test. The expression levels of P2X7R, NLRP3, ASC, and inflammatory factors IL-1β and IL-18 in the prefrontal cortex were detected by Western blot and ELISA. Mitochondrial ultrastructure was observed using transmission electron microscopy, and the ATP levels and reactive oxygen species (ROS) levels were measured. The results showed that the model group mice exhibited significant social impairment, loss of novelty preference, and increased stereotyped behaviors (P<0.01). The expression of P2X7R/NLRP3 pathway-related proteins and inflammatory factors in the prefrontal cortex was significantly upregulated, mitochondrial structure was damaged, ATP content decreased, and ROS levels increased (P<0.01). However, after A-438079 intervention, these behavioral deficits were significantly improved, inflammatory responses were reduced, mitochondrial structure was repaired, energy metabolism function was restored, and ROS production decreased (P<0.05). This indicates that abnormal activation of the P2X7R/NLRP3 pathway participates in the occurrence and development of core behavioral deficits in ASD by exacerbating neuroinflammation and impairing mitochondrial function. Inhibition of P2X7R may effectively break the vicious cycle of “inflammation-mitochondrial damage,” suggesting that this receptor may exert its regulatory role through NLRP3 inflammasome-dependent and potentially independent pathways, and is a potential key target connecting neuroimmunity and energy metabolism. This study provides new experimental evidence for the study of the mechanisms of ASD and the development of intervention strategies.

Key words: purinergic receptor P2X ligand-gated ion channel 7, NOD-like receptor pyrin domain-associated protein 3, autism spectrum disorder, behavior, mitochondria