Neurotrophic Mechanisms in Retinal Ganglion Cell Maturation

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DESCRIPTION (provided by applicant): The goal of the proposed study is to reveal how retinal ganglion cells (RGCs) acquire their dendritic morphology during postnatal development. The complex yet characteristic dendritic structure of RGCs governs their functional properties. For example, morphological specialization in the laminar patterns of RGC dendrites reflects the functional separation of ON and OFF pathways. Recent studies have revealed that dendritic elaboration and refinement of RGCs take place in a subtype-specific manner after eye- opening and that these processes depend differently on visual experience. Experiments in this proposal will study the molecular mechanisms underlying the postnatal development of RGC dendritic structure. Specifically, the investigators will focus on the roles of two neurotrophins, Brain-derived neurotrophic factor (BDNF) and Neurotrophin 3 (NT-3). BDNF and NT-3 signaling through their respective cognate receptor tyrosine kinases, TrkB and TrkC, are known to regulate the survival, development, and function of neurons in the brain. To study how neurotrophin signaling affects RGC dendritic development, the investigators will use several lines of transgenic mice in which RGC structures are delineated in high resolution and BDNF/TrkB and NT-3/TrkC signaling can be manipulated temporally or spatially. The investigators will first determine the developmental profile of RGC dendritic structure before eye-opening and the exact effects of BDNF/TrkB and NT-3/TrkC signaling on this process. Second, the investigators will examine the sensitive periods of BDNF/TrkB and NT-3/TrkC signaling in RGC dendritic maturation and whether the effects of altered neurotrophin signaling are reversible. Finally, using a behavioral test of optomotor responses, the investigators will determine how the neurotrophin-sensitive RGC maturation contributes to the normal development of visual acuity. Together, these studies will provide valuable insights on how neurotrophins affect the establishment and refinement of retinal circuitry, and on the understanding and treatment of retinal disorders resulting from ganglion cell death or abnormal visual experiences, such as uncorrected congenital cataracts and amblyopia. PUBLIC HEALTH RELEVANCE: The long-term goal of our research is to reveal how neurotrophins, the survival factors for neurons, modulate the maturation of structure and function of retinal ganglion cells after birth. These studies are of great clinical importance, because many retinal disorders and visual impairments originate from ganglion cell death or loss of neuronal connectivity during infancy and childhood. Our studies will provide new insights on how neurotrophins could be used to prevent and treat these diseases.