Functional plasticity in retinal degenerative disease

在过去的二十年里，视网膜不仅仅是一个静态的神经元网络，这一点已经变得清晰起来。视网膜 神经元在衰老或疾病过程中改变其属性和连接，这一过程称为视网膜重塑 或者可塑性。然而，调节可塑性的机制以及可塑性对光信号的影响 视网膜和视力仍然不清楚。我们的长期目标是推进视网膜重塑领域 致力于视力恢复疗法的发展，并改善结果。这一目标是通过(I)实现的 确定视网膜中可以促进视力的代偿机制，以及(Ii)量化 光感受器退行性疾病期间视网膜输出和视力的重塑。我们的中心假设 是杆状感官输入的部分损失增加了剩余输入到杆状的传输增益 视网膜中的双极细胞(RBC)以促进视觉，而感觉输入的广泛丧失导致 破坏光信号传输，加剧视力丧失。这一中心假设将得到检验。 在由视紫红质P23H突变引起的常染色体显性遗传性视网膜色素变性小鼠模型中。这个 这个项目的基本原理是，描绘视网膜的代偿机制将产生一个可接近的靶点。 用于促进非自然发生的感光细胞退行性疾病的视力。第二， 关于视网膜建设性和破坏性重塑的影响和时间进程的新认识 VISION将产生有关视力恢复治疗预期结果的关键信息。中环 假设将在两个特定的目的进行检验：1)确定Rod-RBC增加的机制 视网膜退行性疾病早期阶段的信号传递；以及2)决定视网膜内部的影响 感光细胞退行性疾病时光信号传递的重塑。在第一个目标中，一个工作 P23H小鼠通过依赖突触素-1(Syt1)增强视杆-红细胞传递的假说 杆状突触终末的通路将通过使用杆状突触特异性缺失的P23H小鼠来测试 体内/体外视网膜电流图以及膜片钳生理学。此外，这些老鼠将被用来 使用行为方法确定这种补偿机制对视觉的影响。在第二个目标中， 光感受器的遗传沉默和光遗传学将与神经节细胞多电极阵列一起使用 P23H小鼠视网膜内重塑对神经节细胞输出影响的电生理学研究 从早期疾病到晚期疾病的光感受器退化。这项创新性的工作挑战了当前的教条 通过断言在一些视网膜退行性疾病中，视网膜补偿 失去光感受器以维持稳定的输出和视力；以及2)应用遗传和光遗传工具来 确定重塑对视网膜输出信号和视力的因果作用。这项拟议的研究具有重要意义 因为它将改变我们对视网膜可塑性的理解，以及它如何影响视网膜功能 视力，在失明疾病的不同阶段恢复正常视力所需的关键知识。

During the last two decades it has become clear that the retina is not just a static network of neurons. Retinal neurons change their properties and connections during aging or disease in a process termed retinal remodeling or plasticity. However, mechanisms that mediate plasticity, as well as the impact of plasticity on light signaling in the retina and vision are still poorly defined. Our long-term goal is to advance the field of retinal remodeling towards development of vision restoration therapies with improved outcomes. This goal is achieved by (i) determining compensatory mechanisms in the retina that can promote vision, and (ii) quantifying the impact of remodeling on the retinal output and vision during photoreceptor degenerative disease. Our central hypothesis is that a partial loss of sensory input from rods increases the gain of transmission of the remaining input to rod bipolar cells (RBCs) in the retina to promote vision, whereas extensive loss of the sensory input leads to a corruption of the light signal transmission and exacerbation of vision loss. This central hypothesis will be tested in a mouse model of autosomal dominant retinitis pigmentosa caused by the rhodopsin P23H mutation. The rationale of this project is that delineating a compensatory mechanism in the retina will yield an accessible target for promoting vision in photoreceptor degenerative diseases where this does not happen naturally. Secondly, new knowledge about the impact and time course of constructive and destructive remodeling in the retina on vision will generate critical information about the expected outcomes of vision restoration therapies. The central hypothesis will be tested in two specific aims: 1) Determine the mechanism underlying the increase of rod - RBC signal transmission at early stages of retinal degenerative disease; and 2) Determine the impact of inner retinal remodeling on light signal transmission during photoreceptor degenerative disease. In the first aim, a working hypothesis that rod – RBC transmission is potentiated in P23H mice via synaptotagmin-1 (Syt1)-dependent pathway in rod synaptic terminal will be tested by using P23H mice with a rod-specific deletion of Syt1 and in vivo/ex vivo Electroretinogram as well as patch clamp physiology. In addition, these mice will be used to determine the impact of this compensatory mechanism on vision using behavior methods. In the second aim, genetic silencing of photoreceptors and optogenetics will be used together with ganglion cell multielectrode array electrophysiology in P23H mice to evaluate the impact of inner retina remodeling on ganglion cell output during photoreceptor degeneration from early to late-stage disease. This innovative work 1) challenges current dogma of destructive remodeling by asserting that in some retinal degenerative diseases, the retina compensates for the loss of photoreceptors to maintain stable output and vision; and 2) applies genetic and optogenetic tools to determine the causal role of remodeling on retinal output signal and vision. The proposed research is significant because it will transform our understanding of plasticity in the retina and how it impacts retinal function and vision, critical knowledge required for restoring normal vision at different stages of blinding disease.