Spatial and temporal diversity of astrocyte phenotypes in Spinocerebellar ataxia type 1 mice

Abstract

While astrocyte heterogeneity is an important feature of the healthy brain, less is understood about spatiotemporal heterogeneity of astrocytes in brain disease. Spinocerebellar ataxia type 1 (SCA1) is a progressive neurodegenerative disease caused by a CAG repeat expansion mutation in the gene Ataxin1 (ATXN1). We characterized astrocytes across disease progression in the four clinically relevant brain regions, cerebellum, brainstem, hippocampus, and motor cortex of Atxn1154Q/2Q mice, a knock-in mouse model of SCA1. We found brain region specific changes in astrocyte density, GFAP expression and area, early in disease and prior to neuronal loss. Expression of astrocytic core homeostatic genes was also altered in a brain-region specific manner and correlated with neuronal activity indicating that astrocytes may compensate or exacerbate neuronal dysfunction in a brain region specific manner. Late in disease, expression of astrocytic homeostatic genes was reduced in all four brain regions indicating loss of astrocyte functions. We observed spatiotemporal changes in microglia with no obvious correlation with spatiotemporal astrocyte alterations indicating a complex orchestration of glial phenotypes in disease. These results support spatiotemporal diversity of glial phenotypes as an important feature of the brain disease that may contribute to SCA1 pathogenesis in a brain-region and disease stage-specific manner.