CD47 Protects Synapses from Excess Microglia-Mediated Pruning during Development

• Published in: Neuron (Cambridge, Mass.) Vol. 100; no. 1; pp. 120 - 134.e6
• Main Authors: Lehrman, Emily K., Wilton, Daniel K., Litvina, Elizabeth Y., Welsh, Christina A., Chang, Stephen T., Frouin, Arnaud, Walker, Alec J., Heller, Molly D., Umemori, Hisashi, Chen, Chinfei, Stevens, Beth
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 10.10.2018; Elsevier Limited
• Subjects: activity; Animals; Brain; CD47; CD47 Antigen - metabolism; don’t eat me; Electrophysiology; Experiments; Female; Immune system; Immunological synapses; Lateral geniculate nucleus; Localization; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Microglia; Microglia - metabolism; Neurogenesis - physiology; Neuronal Plasticity - physiology; Phagocytosis; Phagocytosis - physiology; protective signal; pruning; Receptors, Immunologic - metabolism; refinement; retinogeniculate system; Signal transduction; SIRPα; Statistical analysis; Synapses - metabolism; Synaptogenesis; pruning; phagocytosis; don’t eat me; activity; protective signal; SIRPα; retinogeniculate system; refinement; CD47; microglia
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2018.09.017

Microglia regulate synaptic circuit remodeling and phagocytose synaptic material in the healthy brain; however, the mechanisms directing microglia to engulf specific synapses and avoid others remain unknown. Here, we demonstrate that an innate immune signaling pathway protects synapses from inappropriate removal. The expression patterns of CD47 and its receptor, SIRPα, correlated with peak pruning in the developing retinogeniculate system, and mice lacking these proteins exhibited increased microglial engulfment of retinogeniculate inputs and reduced synapse numbers in the dorsal lateral geniculate nucleus. CD47-deficient mice also displayed increased functional pruning, as measured by electrophysiology. In addition, CD47 was found to be required for neuronal activity-mediated changes in engulfment, as microglia in CD47 knockout mice failed to display preferential engulfment of less active inputs. Taken together, these results demonstrate that CD47-SIRPα signaling prevents excess microglial phagocytosis and show that molecular brakes can be regulated by activity to protect specific inputs. •“Don’t eat me” signals are developmentally regulated in the dLGN during peak pruning•CD47KO and SIRPαKO mice exhibit increased microglial engulfment•CD47KOs show increased functional pruning and sustained reductions in synapse number•CD47 is localized to more active inputs and required for activity-dependent engulfment Lehrman et al. discover that CD47-SIRPα signaling prevents excess microglial phagocytosis during developmental synaptic pruning. They find that CD47 is required for neuronal activity-mediated changes in microglial engulfment and that mice lacking CD47 display increased structural and functional pruning.