Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways

Abstract

To achieve its precise neural connectivity, the developing mammalian nervous system undergoes extensive activity-dependent synapse remodelling. Recently, microglial cells have been shown to be responsible for a portion of synaptic pruning, but the remaining mechanisms remain unknown. Here we report a new role for astrocytes in actively engulfing central nervous system synapses. This process helps to mediate synapse elimination, requires the MEGF10 and MERTK phagocytic pathways, and is strongly dependent on neuronal activity. Developing mice deficient in both astrocyte pathways fail to refine their retinogeniculate connections normally and retain excess functional synapses. Finally, we show that in the adult mouse brain, astrocytes continuously engulf both excitatory and inhibitory synapses. These studies reveal a novel role for astrocytes in mediating synapse elimination in the developing and adult brain, identify MEGF10 and MERTK as critical proteins in the synapse remodelling underlying neural circuit refinement, and have important implications for understanding learning and memory as well as neurological disease processes. This study describes comprehensive synaptic engulfment by astrocytes, mediating synapse elimination in an activity-dependent manner; this elimination process involves the MEGF10 and MERTK phagocytic pathways and persists into adulthood, with mutant mice that lack these pathways in astrocytes exhibiting a failure to refine retinogeniculate connections during development. Synapse elimination is an important aspect of brain development in which the number of synaptic contacts is reduced in an activity-dependent manner. Glial cells — non-neural cells that perform a variety of roles in the brain — were recently shown to have a role in synapse remodelling, with the phagocytic microglia responsible for a certain proportion of connection refinement, with little else known regarding the mechanisms underlying this. Here, Won-Suk Chung et al. describe comprehensive synaptic engulfment by astrocytes, mediating synapse elimination in an activity-dependent manner. This elimination process involved the MEGF10 and MERTK phagocytic pathways, with transgenic animals lacking these pathways in astrocytes exhibiting a failure to refine retinogeniculate connections during development. These mechanisms also extend into adulthood. This work has implications for our understanding of learning and memory as well as neurological disease processes.