How do Müller Glia Control Retinal Connectivity?

Neural retina is a CNS structure composed of well-organized layers of neurons with distinct functions. The neuroanatomy and circuit-specific synaptic organization of the retina have been extensively studied and a number of neuronal molecular pathways that regulate synaptic connectivity in the retina have been identified; however, neuron-glia interactions that drive synaptic development in the retina are still not understood. Here we studied the requirements of Müller glia (MG)-secreted Thrombospondins (TSP), TSP1 and TSP2, in establishing retinal synaptic connectivity. Using RNA-fluorescence in situ hybridization (RNA-FISH) combined with immunohistochemistry (IHC), we found that MG produce TSP1 and TSP2 in the retina. TSP1 and TSP2 were enriched within the synaptic outer and inner plexiform layers (OPL and IPL, respectively), and their common synaptogenic neuronal receptor, ¿2¿-1, is also enriched at both synaptic layers. To determine the requirement of TSP/¿2¿-1 signaling in retinal synapse development, we utilized transgenic mice that lack ¿2¿-1 (¿2¿-1 KO) or TSP1 (TSP1 KO) or TSP2 (TSP2 KO). Our findings reveal that TSPs and their receptor ¿2¿-1 are critical for formation of retinal excitatory synapses. Interestingly, we found that TSP1 and TSP2 perform non-overlapping roles in regulating retinal synaptic connectivity, indicating that TSP-signaling modulates circuit-specific retinal synapse development.