The proper functioning of the central nervous system (CNS) requires that its many cellular components are connected appropriately, in order to process and encode information specific to each part of the brain. Thus, determining how the CNS is wired up precisely during development is fundamentally important. Although we have gained a significant understanding of the cellular and molecular mechanisms that are critical for circuit development, much has yet to be unraveled. Discovering these mechanisms requires approaches that will elucidate how cells interact with each other to form and maintain connections. Our long term goal is to understand how highly specific synaptic connections are established between the many cell types of the vertebrate retina, largely for 2 reasons: The retina is (1) essential for vision;and (2) its strongly correlated structure and function makes it an excellent model for investigating how neural cricuits are organized during development. In this proposal, we will focus on the first synaptic layer of the retina, the outer plexiform layer (OPL), within which visual signals are first processed in the visual system. In the OPL, photoreceptors contact bipolar cells that then relay signals along distinct pathways to retinal output cells. Horizontal cells modulate information conveyed from photoreceptors. Despite the importance of visual processing by the OPL, little is understood concerning its assembly during development. We propose to use and generate transgenic mice to examine how the various outer retinal cell types interact with each other to establish circuitry in the OPL. We will label photoreceptors, bipolar and horizontal cells in live animals, by causing them to express fluorescent proteins using cell-specific promoters. State-of-the-art optical imaging methods will be applied to visualize and follow how processes of these cells come to form appropriate contact with each other. We will also use and generate mutant mice to address the importance of horizontal cells, which develop earliest, in regulating the structural and functional development of the OPL. Our results should provide a deeper understanding of how interactions between cells lead to the establishment of their circuits, and thus provide further insight into developmental disorders in the nervous system. Our findings could potentially help focus future investigations aimed at designing strategies to re-establish retinal function in trauma or disease.
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