Neuronal plasticity in retinal circuit development and disease

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SUMMARY Neuronal plasticity is high during development and low at maturity. High plasticity enables developing circuits to refine their connections and attain specific functions, whereas low plasticity restricts rewiring in mature circuits, limiting functional recovery from neurodegeneration and injury. Our proposal focuses on three questions: (1) How do cell-type-specific plasticity mechanisms support the development of specific circuits? (2) What controls the maturational switch from high to low plasticity? (3) How can we enhance plasticity of mature neurons to promote functional recovery from neurodegeneration and injury? We will address these questions in retinal bipolar cells. Bipolar cells are second-order neurons of the visual system and relay photoreceptor signals from the outer retina to amacrine and ganglion cells in the inner retina. Bipolar cells lose input when photoreceptors die in retinal degeneration, the most common heritable cause of visual impairment (i.e., > 1:2000 people worldwide). Retinal degeneration, a heterogeneous group of diseases, often progresses slowly, leaving a window of opportunity, in which rewiring of bipolar cells with remaining photoreceptors could rescue vision. In Aim 1 of our proposal, we will characterize the developmental plasticity of three bipolar cell types, which participate in two retinal circuits that support specific visually guided behaviors. Thus, we will link cell-type-specific plasticity mechanisms to the development of specific circuits and the behaviors they support. In Aim 2, we will characterize molecules and mechanisms that contribute to the maturational switch from high to low plasticity in the same bipolar cells. We will translate insights into these molecules and mechanisms into viral tools to restore developmental plasticity to mature neurons. In Aim 3, we will test the ability of these tools to rescue connectivity and function in two mouse models of retinal degeneration. Throughout this proposal, we will use adeno- associated viruses to manipulate plasticity. We will analyze bipolar cell morphology and connectivity by confocal and superresolution imaging. We will monitor circuit function by two-photon Ca2+ imaging and patch clamp electrophysiology, and we will test optokinetic responses and perceptual contrast sensitivity to assess visual function of mice. Together, these studies will provide insights into the expression and control mechanisms of plasticity and translate these insights into strategies to enhance plasticity of mature bipolar cells to rescue vision during retinal degeneration.