Ozone causes depressive-like response through PI3K/Akt/GSK3β pathway modulating synaptic plasticity in young rats

Ozone pollution has been associated with several adverse effects, including memory impairment, intellectual retardation, emotional disturbances. However, the potential mechanisms remain uncertain. The present study aimed to investigate whether ozone (O₃) regulates synaptic plasticity through PI3K/Akt/GSK3β signaling pathway and induces neurobehavioral modifications among the young rats. In vivo, the newborn rats were used to construct the animal model of early postnatal O₃ treatment. In vitro, this study measured the effect of different concentrations of serum from O₃ treated rats on the viability of the PC12 cells, and investigated the modifications of synaptic plasticity and PI3K/Akt/GSK3β signaling pathway in the hippocampus and PC12 cells after O₃ treated. The results revealed significant depression-like behavior and increased hippocampal histopathological damage in the young rats after O₃ treated. Compared with the control group, the expression levels of synaptic related proteins including Drebrin, PSD95, Synaptophysin and PIK3R1, p-Akt, and p-GSK3β were decreased in the O₃ treated group. In vitro assays, a significant reduction in Drebrin, PSD95, Synaptophysin, PIK3R1, p-Akt, and p-GSK3β was found in PC12 cells after O₃ serum treated. While 740Y-P (a specific PI3K activator) administered, the expression levels of Drebrin, PSD95, Synaptophysin, PIK3R1, p-Akt, and p-GSK3β in the 740Y-P + O₃ group were significantly elevated in vivo and vitro compared with the O₃-only group. In addition, miRNAs modulating PIK3R1 were screened on bioinformatics website, the study found aberrant expression of miR-221-3p in the hippocampus and serum of O₃ treated group. Inhibition of miR-221-3p expression effectively reversed the reduction of Drebrin, PSD95, Synaptophysin, PIK3R1, p-Akt, and p-GSK3β in PC12 cells induced by O₃ treatment. Altogether, these studies indicate that O₃ restrained the expression of PI3K/Akt/GSK3β signaling pathway and impaired synaptic plasticity that resulted in depressive-like behavior in young rats. Moreover, miR-221-3p plays an important role in this procedure by regulating PIK3R1.