Ganglion Cell Function in Retinal Disease

神经节细胞在视网膜疾病中的功能

• 批准号: 8327980
• 负责人: Maureen A McCall
• 金额: $ 1.86万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-02-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8327980
• 关键词: Address; Affect; Afferent Neurons; Age; Amacrine Cells; Cations; Cell physiology; Cells; Data; Defect; Detection; Development; Developmental Delay Disorders; Diagnosis; Disease; Electroretinography; Eye; Functional disorder; Funding; Genes; Glutamate Receptor; Glutamates; Goals; Human; Individual; Investigation; Lead; Light; Masks; Mediating; Modeling; Motion; Mus; Mutant Strains Mice; Mutation; Nature; Nervous system structure; Night Blindness; Pathway interactions; Patients; Pattern; Peripheral; Phenotype; Photoreceptors; Phylogenetic Analysis; Play; Primates; Principal Investigator; Process; Property; Research; Rest; Retina; Retinal; Retinal Diseases; Retinal Ganglion Cells; Role; Sensory; Signal Transduction; Stimulus; Synapses; Testing; Therapeutic; Vision; Visual; Visuospatial; Work; disease phenotype; ganglion cell; information processing; luminance; mouse model; mutant; neural circuit; programs; public health relevance; receptive field; receptor; research study; response; scaffold; vision development; visual process; visual processing

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.

描述（由申请人提供）：本研究的目标是了解调节视网膜神经节细胞视觉功能和空间组织发育的信号机制，以及它们在视网膜疾病中如何改变。正常视力始于视网膜，并由光感受器检测光启动。信息流的并行路径在光感受器与去极化和超极化双极细胞之间的第一个突触处启动，其检测暗适应和光适应条件下的亮度增加和减少和/或视力。因此，这些路径扩展了强度域中信息处理的动态范围，并增加了针对显着环境特征（例如运动、方向和大小）的信息处理的专业化。这些回路内的信号传导通过视网膜外层和内层的抑制输入而得到完善，这些相互作用最终形成并定义了视网膜神经节细胞的感受野组织。感受野是所有物种的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，了解感受野特性如何发展是了解视网膜视觉功能的关键，而神经节细胞是至关重要的部分，因为它们既代表了所有视网膜处理的巅峰，又代表了其余视觉处理的支架。由于基本的射频空间组织在神经节细胞视觉反应开始时就已经存在，因此其发展的过程相对难以研究。先天性静止性夜盲症 (CSNB) 患者和小鼠模型中出现的视觉缺陷充分表明，正常视力需要通过去极化和超极化途径发出信号，其中去极化双极细胞处理被消除。我们拥有三种独特的 CSNB1 小鼠模型，我们将继续使用它们来探测 CSNB 下的突触电路，其中保留了正常的光感受器功能。三个突变体中 GC 自发反应和视觉诱发反应变化的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独特的机会。感受野组织的系统发育保守性表明我们在小鼠中的发现将与灵长类动物周边视网膜处理相关。我们认为，这些小鼠模型的表征代表了其他小鼠或脊椎动物模型无法提供的重要机会，并且代表了我们理解 CSNB1 疾病机制以及正常视网膜发育和功能的关键一步。 公共健康相关性：该提案旨在了解控制视网膜视觉发育的机制，并研究当视网膜信息处理的并行途径之一消除信号传导时下游突触机制的变化。一个重点是了解完全先天性静止性夜盲症发生的确切变化，这是一种不涉及光感受器功能障碍或形态缺陷的视网膜疾病。第二个重点是了解调节正常视网膜功能发育的基本过程，特别是神经节细胞。我们相信，我们的结果将指导恢复或挽救 CSNB 的诊断和治疗方法，并且也与所有年龄段人群的其他致盲疾病相关。