The classical complement cascade mediates CNS synapse elimination. During development, the formation of mature neural circuits requires the selective elimination of inappropriate synaptic connections. This study shows that C1q, the initiating protein of the classical complement cascade, is expressed by postnatal neurons in response to immature astrocytes and is localized to synapses throughout the postnatal CNS and retina. Mice deficient in C1q or the downstream complement protein C3 exhibit large sustained defects in CNS synapse elimination, as shown by the failure of anatomical refinement of retinogeniculate connections and the retention of excess retinal innervation by lateral geniculate neurons. Neuronal C1q is normally downregulated in the adult CNS; however, in a mouse model of glaucoma, C1q becomes upregulated and synaptically relocalized in the adult retina early in the disease. These findings support a model in which unwanted synapses are tagged by complement for elimination and suggest that complement-mediated synapse elimination may become aberrantly reactivated in neurodegenerative disease. The study identifies an unexpected role for astrocytes and the classical complement cascade in mediating CNS synapse elimination in the retinogeniculate pathway. By gene profiling, they found that all three chains of the complement protein C1q are strongly upregulated when purified RGCs are exposed to astrocytes. C1q is the initiating protein of the classical complement cascade, which is part of the innate immune system. When C1q binds to and coats dead cells, pathogens, or debris, it triggers a protease cascade, leading to the deposition of the downstream complement protein C3. Opsonization with activated C3 fragments leads to cell or debris elimination in one of two ways. The study shows that complement proteins opsonize or tag CNS synapses during a discrete window of postnatal development and that the complement proteins C1q and C3 are required for synapse elimination in the developing retinogeniculate pathway. They also show that C1q becomes aberrantly upregulated and relocalized to adult retinal synapses in a mouse model of glaucoma at an early stage of the disease prior to overt neurodegeneration, suggesting that the complement cascade also mediates synapse loss in glaucoma and other CNS neurodegenerative diseases. The study provides evidence that C1q is localized to synapses in the developing retina and brain during the period of synaptic pruning. C1q is required for retinogeniculate refinement. The localization of C1q to developing synapses, together with C1q's known role in eliminating unwanted cells and debris, suggested a role for C1q in mediating synapse elimination. To test this hypothesis, they used a combination of neuroanatomical and electrophysiological techniques to investigate the refinement and elimination of retinogeniculate synapses in the dLGN of mice that lack the A chain of C1q (CThe classical complement cascade mediates CNS synapse elimination. During development, the formation of mature neural circuits requires the selective elimination of inappropriate synaptic connections. This study shows that C1q, the initiating protein of the classical complement cascade, is expressed by postnatal neurons in response to immature astrocytes and is localized to synapses throughout the postnatal CNS and retina. Mice deficient in C1q or the downstream complement protein C3 exhibit large sustained defects in CNS synapse elimination, as shown by the failure of anatomical refinement of retinogeniculate connections and the retention of excess retinal innervation by lateral geniculate neurons. Neuronal C1q is normally downregulated in the adult CNS; however, in a mouse model of glaucoma, C1q becomes upregulated and synaptically relocalized in the adult retina early in the disease. These findings support a model in which unwanted synapses are tagged by complement for elimination and suggest that complement-mediated synapse elimination may become aberrantly reactivated in neurodegenerative disease. The study identifies an unexpected role for astrocytes and the classical complement cascade in mediating CNS synapse elimination in the retinogeniculate pathway. By gene profiling, they found that all three chains of the complement protein C1q are strongly upregulated when purified RGCs are exposed to astrocytes. C1q is the initiating protein of the classical complement cascade, which is part of the innate immune system. When C1q binds to and coats dead cells, pathogens, or debris, it triggers a protease cascade, leading to the deposition of the downstream complement protein C3. Opsonization with activated C3 fragments leads to cell or debris elimination in one of two ways. The study shows that complement proteins opsonize or tag CNS synapses during a discrete window of postnatal development and that the complement proteins C1q and C3 are required for synapse elimination in the developing retinogeniculate pathway. They also show that C1q becomes aberrantly upregulated and relocalized to adult retinal synapses in a mouse model of glaucoma at an early stage of the disease prior to overt neurodegeneration, suggesting that the complement cascade also mediates synapse loss in glaucoma and other CNS neurodegenerative diseases. The study provides evidence that C1q is localized to synapses in the developing retina and brain during the period of synaptic pruning. C1q is required for retinogeniculate refinement. The localization of C1q to developing synapses, together with C1q's known role in eliminating unwanted cells and debris, suggested a role for C1q in mediating synapse elimination. To test this hypothesis, they used a combination of neuroanatomical and electrophysiological techniques to investigate the refinement and elimination of retinogeniculate synapses in the dLGN of mice that lack the A chain of C1q (C