Cell surface markers identify astrocyte subpopulations in the adult hippocampus with a heterogeneous response to aging

Astrocyte diversity is currently expanding both between and within specific brain regions. Here, we assessed the spatial distribution and transcriptomic profile of two hippocampal astrocyte subpopulations, defined by combinatorial expression of the cell surface astrocyte markers ACSA-1 or GLAST/SLC1A3, and ACSA-2 or ATP1B2. Fluorescence activated cell sorting and genome-wide transcriptomics by bulk RNAseq uncovered distinct transcriptional signatures of the two astrocyte subsets and highlighted heterogeneous responses during aging. The most abundant ATP1B2/GLAST double-positive astrocytes corresponded to mature glial cells with increased protein glycosylation and stable gene expression patterns. Signatures related to mitochondrial respiration and cholesterol metabolism were induced during aging in ATP1B2 single-positive astrocytes, while cell adhesion genes from the {gamma}-protocadherin cluster were repressed in double-positive astrocytes. Heterochronic co-culture assays with primary neurons show the loss of synaptogenic function of old ATP1B2/GLAST astrocytes. Our results complement previous studies demonstrating the presence of morphological and molecular astrocyte heterogeneity within the hippocampus, and uncover differences among astrocyte subsets in their transcriptomic response to aging.