CD51 expression delineates functionally distinct astrocyte subpopulations in neural circuits

Astrocytes execute a diverse range of tasks that facilitate brain physiology, raising the possibility that these diverse astrocytic roles are enabled by functionally distinct subtypes1,2. Recent studies identified molecular diversity amongst astrocytes3, however whether this molecular heterogeneity reflects specialized astrocyte subpopulations with distinct functions remains unknown. Leveraging prior molecular and functional studies4, we generated a CD51-FLP mouse line that enables the direct comparison of functional properties between CD51+ and CD51- astrocyte subpopulations in neural circuits in vivo. Here we show that CD51+ and CD51- astrocytes are endowed with unique morphological, physiological, and developmental properties in both the cortex and hippocampus. Functional studies demonstrate that CD51+ astrocytes selectively promote synapse formation in the developing cortex and circuit plasticity in the hippocampus. Mechanistically, we found that CD51+ astrocytes function through glypican 6 to promote synapse formation in the cortex, while CD51 itself drives circuit plasticity in the hippocampus. Applying these findings to brain injury, we found that exploiting the unique properties of CD51+ astrocytes promotes functional recovery after stroke through enhanced synaptic remodeling. Taken together, our studies identify specialized astrocyte subpopulations that exhibit distinct functional properties in the developing, mature, and injured brain. Overall design: Cortex and hippocampus were dissected from CD51-Flp; Rosa-CAG-FSF-tdTomato mice and tdTomato+/GFP+ (CD51+ astrocytes) and tdTomato-/GFP+ (CD51- astrocytes) were FACS isolated. RNA was extracted from FACS isolated populations and prepared for RNA-sequencing.