543. MODULATION OF BRAIN FUNCTIONS BY GLIAL RESET

Abstract Background Microglia actively regulate brain function through synaptic and neural network remodeling. Abnormalities in microglia modulate the regulation of these neurons and contribute to the etiology of psychiatric and neurodegenerative diseases. Therefore, we developed a strategy to replace microglia by resetting or transplanting microglia as a therapeutic strategy for these diseases and tested its therapeutic efficacy. Aims & Objectives The aim of of this study is to elucidate the impact of microglial replacement on the pathogenesis of animal models of disease. The objectives are: 1) to develop an accurate microglial replacement method, 2) to demonstrate in animal models that microglial replacement can be a therapeutic strategy for various brain diseases, and 3) to elucidate the molecular mechanisms of the therapeutic effects of microglial replacement. Method Microglia require colony stimulating factor 1 receptor (CSF1R) signaling for survival. We used two of microglia replacement methods: microglia removal/regeneration by turning CSF1R antagonists ON and OFF (reset) and microglia transplantation. The effects of microglial replacement were analyzed molecularly, biochemically, and behaviorally using mainly the Alexander disease (AxD) model. Results Microglial reset was enabled by turning ON/OFF of CSF1R antagonists (PLX5622 or PLX3397). Microglial transplantation was also possible by combining reset with tranasal microglial transplantation. In experiments with AxD model mice, removal of microglia exacerbated the disease, but reset of microglia improved the disease. Thus, it was shown that microglia have a protective effect against AxD pathology and that the effect is enhanced by replacement. RNA sequencing analysis revealed that the expression of various inflammatory molecules is upregulated in the AxD brain, and that microglial replacement dramatically suppresses these inflammatory effects. The effects of microglial replacement on mouse models of autism will also be reported. Discussion & Conclusions Microglia can be easily, safely, and reproducibly replaced by turning ON/OFF of CSF1R antagonists (Reset) and by microglia transplantation combined with the Reset and microglia intranasal transplantation. Microglial abnormalities have been observed in the brains of various animal models of brain diseases. Removal of these microglia alone does not necessarily result in improvement of the disease state. This is because microglia are heterogenous and play not only toxic but also beneficial roles. In fact, the replacement of microglia and restoring them to normality improved the disease state. Thus, microglial replacement may be a therapeutic strategy for various brain diseases, including the AxD model. In the case of the AxD model, the molecular mechanism of the therapeutic effect of microglia replacement was found to be mainly the inhibition of neuroinflammation.