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 still not clear how their activation affects the transcriptome of other brain cells such as microglia and neurons. Engineered G protein-coupled receptors called Designer Receptors Exclusively Activated by Designer Drugs (DREADDS) make it possible to selectively activate specific cell types, such as neurons and astrocytes. By combining the selective activation of astrocytes with single cell RNA sequencing, we were able to study transcriptional changes that occur in response to the activation of astrocytes at the single cell level. Interestingly, our data shows that long-term activation of astrocytes in healthy mice results in dramatic alteration in the transcriptome of astrocytes and microglia. Genes that were differentially expressed in these Gq-DREADD-activated astrocytes were involved in neurogenesis and low density lipoprotein particle biology, while those in the microglia were involved in the response to lipoproteins, and the migration and chemotaxis of immune cells. Furthermore, network analysis showed that Gq-DREADD-mediated activation in astrocytes resulted in an upregulation of genes involved in the G protein-coupled receptor signaling pathway and calcium ion homeostasis. This confirmed the activation of astrocytes through the expressed DREADDS. Our findings show the importance of considering the transcriptomic alteration in microglia and neurons after the activation of astrocytes in models. Therefore, our data will serve as a resource for the broader neuroscience community.