Chemogenetic activation of astrocytes in the hippocampus and cortex changes the transcriptome of microglia and other cell types.

Astrocytes are the most common glial cell type in the brain, yet, it is unclear how their activation affects the transcriptome of neighboring cells. Engineered G protein-coupled receptors (GPCRs) called Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) enable selective activation of specific cell types, such as astrocytes. Here, we combine activation of astrocytes in the hippocampus and cortex of healthy mice with single-cell RNA sequencing. Our data show that long-term activation of astrocytes dramatically alters the transcriptome of astrocytes and microglia. Genes that were differentially expressed in Gq-DREADD-activated astrocytes are involved in neurogenesis and low-density lipoprotein particle biology, while those in the microglia were involved in lipoprotein handling, purinergic receptor activity, and immune cell migration and chemotaxis. Furthermore, network analysis showed that Gq-DREADD-mediated activation in astrocytes resulted in an upregulation of genes involved in the GPCR signaling pathways and calcium ion homeostasis, confirming astrocyte activation. This dataset will serve as a resource for the broader neuroscience community, and our findings highlight the importance of studying transcriptomic alterations in microglia after astrocyte activation in vivo.