CD51 delineates functionally distinct astrocyte subtypes in neural circuits

Astrocytes perform a diverse range of tasks that facilitate brain physiology, raising the possibility that these diverse astrocytic roles are enabled by functionally distinct subtypes^1,2. Recent studies identified molecular diversity among astrocytes³; however, whether this molecular heterogeneity reflects specialized astrocyte subpopulations with distinct functions remains unclear. Here, on the basis of previous molecular and functional studies⁴, we generated a CD51-FLP mouse line that enables direct comparison of the functional properties between CD51⁺ and CD51^- astrocyte subpopulations in neural circuits in vivo. We show that CD51⁺ and CD51^- astrocytes have 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 CD51⁺ astrocytes promote functional recovery after stroke through enhanced synaptic remodelling. Taken together, our studies identify specialized astrocyte subpopulations that exhibit distinct functional properties in the developing, mature and injured brain.