Thrombospondins (TSPs) are large, extracellular matrix proteins that mediate cell-cell and cell-matrix interactions. This study identifies TSPs as astrocyte-secreted proteins that promote synaptogenesis in the central nervous system (CNS). Using rat retinal ganglion cell (RGC) cultures, the authors found that TSPs induce the formation of ultrastructurally normal synapses that are presynaptically active but postsynaptically silent. These synapses are functionally active, as indicated by increased vesicular recycling and glutamate release. TSPs work in concert with other, unidentified astrocyte-derived signals to produce functional synapses. In vivo, TSP1 and TSP2 are expressed by astrocytes in the developing brain and are downregulated in the adult brain. Mice lacking both TSP1 and TSP2 exhibit a significant reduction in synaptic puncta at postnatal day 8 and 21. These findings suggest that TSPs act as a permissive switch, timing CNS synaptogenesis by enabling neuronal molecules to assemble into synapses during a specific window of development.Thrombospondins (TSPs) are large, extracellular matrix proteins that mediate cell-cell and cell-matrix interactions. This study identifies TSPs as astrocyte-secreted proteins that promote synaptogenesis in the central nervous system (CNS). Using rat retinal ganglion cell (RGC) cultures, the authors found that TSPs induce the formation of ultrastructurally normal synapses that are presynaptically active but postsynaptically silent. These synapses are functionally active, as indicated by increased vesicular recycling and glutamate release. TSPs work in concert with other, unidentified astrocyte-derived signals to produce functional synapses. In vivo, TSP1 and TSP2 are expressed by astrocytes in the developing brain and are downregulated in the adult brain. Mice lacking both TSP1 and TSP2 exhibit a significant reduction in synaptic puncta at postnatal day 8 and 21. These findings suggest that TSPs act as a permissive switch, timing CNS synaptogenesis by enabling neuronal molecules to assemble into synapses during a specific window of development.