Ganglion Cell Function in Retinal Disease

描述（由申请人提供）：本研究的目的是了解调节视觉功能和视网膜神经节细胞空间组织发育的信号机制，以及它们在视网膜疾病中的改变。正常的视力开始于视网膜，由感光器探测到光线而产生。在光感受器和去极化和超极化双极细胞之间的第一个突触上启动了平行的信息流通路，这些细胞在黑暗和适应光的条件下检测亮度的增加和减少和/或视觉。因此，这些路径扩展了强度域信息处理的动态范围，并增加了对显著环境特征（如运动、方向和大小）的信息处理的专业化。这些电路中的信号通过外部和内部视网膜的抑制输入而得到完善，这些相互作用最终决定了视网膜神经节细胞的感受野组织。感受野是所有物种中所有感觉神经元共有的基本属性。它定义了每个细胞编码的环境刺激的类型和范围。因此，理解感受野特性如何发展是理解视网膜视觉功能的关键，而神经节细胞是至关重要的一部分，因为它们既代表了所有视网膜处理的高潮，又代表了其余视觉处理的支架。由于基本RF空间组织在神经节细胞的视觉反应开始时已经存在，因此其发展背后的过程相对难以研究。正常视力需要通过去极化和超极化通路的信号，这在先天性静止性夜盲症（CSNB）患者和小鼠模型中发生的视觉缺陷中得到了充分的证明，去极化双极细胞处理被消除了。我们有三种独特的CSNB1小鼠模型，我们将继续使用它们来探测CSNB背后的突触回路，其中正常的光感受器功能被保留。在三种突变体中，自发和视觉诱发反应的变化性质为研究感受野组织和神经节细胞信号传导的发展提供了一个独特的开端。感受野组织的系统发育保护表明，我们在小鼠中的发现将与灵长类动物外周视网膜加工有关。我们认为，这些小鼠模型的表征代表了一个重要的机会，而不是其他小鼠或脊椎动物模型所提供的，并且代表了我们理解CSNB1疾病机制和正常视网膜发育和功能的关键一步。

DESCRIPTION (provided by applicant): The goals of this research are focused on understanding signaling mechanisms that regulate the development of visual function and spatial organization of retinal ganglion cells and how they are altered in retinal disease. Normal vision begins in the retina and is initiated by photoreceptor detection of light. Parallel pathways of information flow are initiated at the first synapse between photoreceptors and depolarizing and hyperpolarizing bipolar cells, which detect luminance increases and decreases and/or vision under dark- and light-adapted conditions. As a result, the pathways extend the dynamic range of information processing in the intensity domain, and increase specialization of information processing for salient environmental features, e.g., motion, direction and size. Signaling within these circuits is refined by inhibitory inputs in the outer and inner retina and these interactions culminate in and define the receptive field organization of the retinal ganglion cells. The receptive field is a basic property, shared across all sensory neurons in all species. It defines the types and range of environmental stimuli that each cell encodes. Thus, understanding how receptive field properties develop is key to understanding visual function in the retina and the ganglion cells are a vital part because they represent both the culmination of all retinal processing and the scaffold for the rest of visual processing. Because basic RF spatial organization is already present at the onset of visual responses in ganglion cells, the processes underlying their development have been relatively intractable to investigation. That normal vision requires signaling through the depolarizing and hyperpolarizing pathways is amply indicated by the visual defects that occur in patients with and mouse models of congenital stationary night blindness (CSNB), where depolarizing bipolar cell processing is eliminated. We have three unique mouse models of CSNB1 that we will continue to use to probe the synaptic circuitry underlying CSNB, in which normal photoreceptor function is retained. The nature of the changes in spontaneous and visually-evoked responses across GCs in the three mutants provides a unique opening to study the development of receptive field organization and ganglion cell signaling. The phylogenetic conservation of receptive field organization suggests that our findings in the mouse will be relevant to primate peripheral retinal processing. We suggest that the characterization of these mouse models represents a significant opportunity, not afforded by other mouse or vertebrate models and represents a critical step in our understanding both the disease mechanisms in CSNB1 and normal retinal development and function. PUBLIC HEALTH RELEVANCE: This proposal seeks to understand the mechanisms that govern the development of vision in the retina and to investigate the changes in the downstream synaptic mechanisms when signaling is eliminated from one of the parallel pathways of information processing in the retina. One focus is to understand the exact changes that occur in complete congenital stationary night blindness, a retinal disease that does not involve photoreceptor dysfunction or morphological defects. A second focus is to understand the fundamental processes that regulate the development of normal retinal function, particularly in the ganglion cells. We believe that our results will guide diagnosis and therapeutic approaches to restore or rescue CSNB and also will be relevant to other blinding diseases in people of all ages.