miR-183/96/182 Cluster Negatively Targets mTOR to Exacerbate Learning and Memory Impairment Caused by Combined...

The neurotoxicants fluorine (F) and aluminium (Al) exert detrimental effects on the nervous system. Fluorine and aluminium (FA) commonly coexist in both natural and anthropogenically polluted environments and have been associated with impairments in learning and memory functions. However, the underlying mechanisms remain to be fully elucidated. Our previous study demonstrated that excessive exposure to FA induces impairments in learning and memory, accompanied by neuronal apoptosis as well as altered expression levels of miR-183, miR-96, and miR-182, which constitute the miR-183/96/182 cluster (miR-183c), in the hippocampus. The aim of this study is to elucidate the molecular mechanisms underlying neuronal apoptosis through which FA induces impairments in learning and memory, using a second-generation (F2) rat model and an NG108-15 cell model exposed to FA with or without miR-183c inhibitor. Apoptosis levels were assessed using flow cytometry, while the expression of miR-183c and the mTOR/P70S6K signaling pathway was evaluated by quantitative real-time PCR (qRT-PCR) and/or western blotting (WB). Our results demonstrate that FA up-regulates miR-183c, thereby inhibiting the expression of the mTOR/P70S6K pathway, leading to learning and memory deficits. However, the administration of a miR-183c inhibitor reversed these effects. To the best of our knowledge, this study is the first to establish a link between FA-induced learning and memory impairments and the activation of miR-183c, which suppresses the mTOR/P70S6K pathway. These findings provide evidence that miR-183c represents a promising therapeutic target for mitigating FA-induced neurotoxicity.