How Do Muller Glia Control Circuit-Specific Retinal Synaptogenesis?

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Synapses are the basic functional units of the central nervous system (CNS). Synaptic dysfunction and synapse loss are hallmarks of neurological disorders including retinal degeneration. However, there currently are no effective therapies that can repair or regenerate these synaptic impairments. Therefore, my long- term goal is to develop cell- and gene-based therapies to repair and/or regenerate these impaired synaptic circuits. In particular, I aim to identify novel cellular and molecular targets for the treatment of retinal degenerative diseases such as age-related macular degeneration and glaucoma. Recent studies have shown that glial cells are important regulators of synapse formation, maintenance and function in the brain. Particularly, astrocytes, major glia cell type in brain, secrete thrombospondin (TSP) family proteins that induce excitatory synapse formation. Unlike brain, Muller glia (MG) are the major glial cell type of the retina, however, how MG regulate neuronal connectivity in the retina remains unclear. In my preliminary experiments, I found that MG secretes TSP1 and TSP2 during early development of the retinal circuitry. TSP1, TSP2 and their synaptogenic receptor α2δ-1 are enriched in the outer and inner plexiform synaptic layers (OPL and IPL, respectively) of the retina. Transgenic mice lacking α2δ-1 (α2δ-1 KO) have dramatically decreased number of synapses in the IPL further supporting their involvements in retinal circuitry development. Particularly, TSP1 is specifically localized at two synaptic sublaminae within the IPL. In vitro studies using purified Retinal Ganglion Cell (RGC) cultures demonstrated that TSP1 specifically promotes synapse formation of On-Off Direction-Selective RGCs (ooDSGCs). TSP1-induced synaptogenesis is inhibited by a function-blocking antibody against Integrin β1, another known receptor of TSP1 that is enriched in ooDSGCs. On the other hand, TSP2 induces formation of synapses onto all RGCs. Based on these findings, I hypothesize that, in the retina, MG-secreted TSPs control different aspects of retinal excitatory synapse development through their common receptor α2δ-1. I further postulate that TSP1 regulates formation of ooDSGCs connectivity through an interaction with Integrin β1 which confers circuit specificity. To test these hypotheses, here I propose two specific aims; 1) To determine the requirement of MG-secreted TSP1 and 2 and their common synaptogenic receptor α2δ-1 for retinal synapse development and function. 2) To determine the role of TSP1/Integrin β1 interaction for the formation of On-Off DSGC specific circuitry. The proposed studies would provide a significant step forward in our understanding of how MG control retinal synaptic development in a circuit specific manner and also would facilitate development of novel therapeutic strategy to repair impaired synaptic circuits. !