CNSC-19. HYPOXIA-INDUCED NEURONAL ACTIVITY IN GLIOMA PATIENTS POLARIZES MICROGLIA BY POTENTIATING RNA M6A DEMETHYLATION

Abstract

Abstract Neuronal activity in the brain has been reported to promote the malignant progression of glioma cells via nonsynaptic paracrine and electrical synaptic integration mechanisms. However, the interaction between neuronal activity and the immune microenvironment in glioblastoma (GBM) remains largely unclear. In this study, by applying chemogenetic techniques, we enhanced and inhibited neuronal activity in vitro and in a mouse model to study how neuronal activity regulates microglial polarization and affects GBM progression. Here, we demonstrate that hypoxia induces glioma stem cells (GSCs) to produce glutamate, which activates local neurons. The hypoxia-induced neuronal activity promotes GBM progression by facilitating microglial M2 polarization. We found that when microglia were co-cultured with activated neurons, the level of RNA m6A methylation in microglia was impaired, which subsequently induced microglial M2 polarization. In the mouse model, cortical neuronal activation promoted regional microglial M2 polarization while cortical neuronal inhibition decreased regional microglial M2 polarization in GBM xenografts. Together, these findings indicate that hypoxic GSC-induced neuronal activation promotes GBM progression by polarizing microglia via decreasing their m6A methylation levels.