Ganglion Cell Function in Retinal Disease

描述(申请人提供)：本研究的目标是了解调节视觉功能发育和视网膜神经节细胞空间组织的信号机制，以及它们在视网膜疾病中是如何改变的。正常的视觉始于视网膜，开始于光感受器对光的探测。平行的信息流通路是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启动的，它们在暗适应和光适应的条件下检测亮度的增加和减少和/或视觉。结果，路径扩展了强度域中信息处理的动态范围，并增加了针对显著环境特征的信息处理的专门化，例如运动、方向和大小。这些回路中的信号由视网膜外部和内部的抑制性输入来精炼，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场组织。感受野是一种基本属性，在所有物种的所有感觉神经元中都是共享的。它定义了每个细胞编码的环境刺激的类型和范围。因此，了解感受野的特性是理解视网膜和神经节细胞视觉功能的关键，因为它们既是所有视网膜加工的顶峰，也是其余视觉加工的支架。由于基本的射频空间组织在神经节细胞的视觉反应开始时就已经存在，其潜在的发展过程一直是相对难以研究的。这种正常的视觉需要通过去极化和超极化的通路传递信号，这一点在先天性静止性夜盲(CSNB)患者和小鼠模型中出现的视觉缺陷中得到了充分的证明，在这种情况下，去极化的双极细胞处理被消除。我们有三个独特的CSNB1小鼠模型，我们将继续使用它们来探测CSNB背后的突触电路，其中保留了正常的光感受器功能。这三个突变体在跨越GC的自发和视觉诱发反应中的变化本质为研究感受野组织和神经节细胞信号的发展提供了独特的机会。感受野组织的系统发育保守表明，我们在小鼠身上的发现将与灵长类外周视网膜处理相关。我们认为，这些小鼠模型的特征代表了一个重要的机会，这是其他小鼠或脊椎动物模型所无法提供的，并且代表着我们在理解CSNB1的疾病机制和正常的视网膜发育和功能方面迈出的关键一步。 与公共健康相关：这项提议试图了解支配视网膜视觉发展的机制，并研究当信号从视网膜中的一条平行信息处理路径上消除时，下游突触机制的变化。一个重点是了解完全性先天性静止性夜盲发生的确切变化，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展的基本过程，特别是在神经节细胞中。我们相信，我们的结果将指导诊断和治疗方法，以恢复或抢救CSNB，也将相关的其他致盲疾病在所有年龄的人。

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.