Thrombospondin-1 Promotes Circuit-Specific Synapse Formation via β1-Integrin

SUMMARYGlial cells regulate synaptic connectivity during development, but whether they selectively instruct the formation of specific synaptic circuits is not known. Here we show that the major perisynaptic glia of the retina, the Muller glia (MG), control the proper establishment of the direction-selective (DS) circuit by a synaptogenic protein, Thrombospondin 1 (TSP1). We found that TSP1 promotes excitatory synapse formation specifically in on-off Direction-Selective retinal Ganglion Cells (ooDSGCs). Lack of TSP1 leads to reduced synapse formation within the inner plexiform sublayers containing DS-circuit, resulting in deficits of ooDSGC function. Even though pan-TSP receptor, α2δ-1, interaction is required for TSP1-induced synapse formation, the ooDSGC-subtype specificity of TSP1 is conferred by a second neuronal TSP1 receptor, β1-Integrin. Furthermore, conditional deletion of β1-Integrin in ooDSGCs results in diminished excitatory synapse formation without disturbing laminar organization showing that MG-secreted TSP1 controls circuit-specific synapse formation via β1-Integrin.