Microglial Ca<sup>2+</sup> signals in Alexander disease model

Abstract

Alexander disease (AxD) is an intractable neurodegenerative disorder caused by GFAP mutations. AxD is a primary astrocyte disease with the pathological hallmark of Rosenthal fibers within astrocytes. AxD astrocytes show several abnormal phenotypes. Our previous study has shown that AxD astrocytes in the model mice show aberrant Ca2+ signal that was a cause of etiology of AxD. In addition, we recently found that microglia in AxD mice also exhibited aberrant Ca2+ signals. Using Iba1-GCaMP6f-hGFAP mice, an AxD model mice for microglial Ca2+ imaging, we studied microglial Ca2+ signals with 2 photon microscopy. We found that microglial Ca2+ signals were dramatically enhanced in AxD mice with more frequent Ca2+ signals in both the processes and cell bodies. Such increases in Ca2+ signals were inhibited by P2Y12R antagonist but not by TTX, suggesting that these enhancement should be independent of neuronal activity, but dependent on extracellular ATP-mediated signals. Thus, we think that these microglial abnormal Ca2+ signals would be caused by aberrant Ca2+ signals in astrocytes. In addition, we already showed that microglia play a protective role in AxD pathology, indicating an importance of microglia-astrocytes communication. Furthermore, to explore how these aberrant AxD microglial Ca2+ signals are related to AxD pathology, we performed dual Ca2+ imaging of astrocytes and microglia in AxD model in combination with genetic expression profiling by transcriptome analysis. This approach of the research would be critical for understanding the molecular mechanism of which microglia are associated with AxD pathogenesis.