Mechanisms, functions and utility of RGC oscillation in retinal deafferentation mouse models

视网膜传入神经阻滞小鼠模型中 RGC 振荡的机制、功能和效用

• 批准号: 9327552
• 负责人: Ching-Kang Jason Chen
• 金额: $ 39.63万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-30 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9327552
• 关键词: Adult; Affect; Aging; Amacrine Cells; Biological Process; Brain; Cells; Characteristics; Cone; Coupled; Coupling; Deafferentation procedure; Development; Electroretinography; Ensure; Exhibits; Eye; Foundations; Future; Gap Junctions; Genes; Glutamate Receptor; Glutamates; Goals; Immunologic Markers; Individual; Investigation; Ipsilateral; Kinetics; Knock-out; Knowledge; Light; Light Cell; Maintenance; Masks; Mediating; Membrane; Membrane Potentials; Modeling; Morphology; Mus; Night Blindness; Outcome; Photoreceptors; Physiological; Potassium Channel; Predisposition; Property; Resources; Rest; Retina; Retinal; Retinal Degeneration; Retinal Diseases; Retinal Ganglion Cells; Role; Source; Stimulus; Strychnine; Surveys; Synapses; Testing; Tracer; Transgenic Organisms; Visual system structure; aged; base; cell type; connexin 36; flupirtine; genetic manipulation; insight; mature animal; mouse model; novel; patch clamp; photoreceptor degeneration; presynaptic; response; retinal neuron; retinogeniculate; starburst amacrine cell

The long-term goal of this application is to elucidate the mechanisms and functions of inner retina oscillation in development and maintenance of the visual system. The proposal is based on the existence of two independent oscillation mechanisms in adult retina. We hypothesize that these oscillation mechanisms are built-in function of the retina, masked by glutamate released by photoreceptor in normal situation but emergent under deafferentation conditions such as photoreceptor degeneration and complete congenital stationary night blindness to ensure stable connection between the eye and the brain. We have found that deleting connexin 36 (Cx36) but not Cx45 genes can silence retinal oscillation. We have also preliminarily tested mice with photoreceptor degeneration but without Cx36 expression and found that retinogeniculate projections become abnormal. Since retinal oscillation appears to have a biological function, it is important to know mechanistic details of the two mechanisms. Aim-1 will thus focus on delineating the cellular origin of the less understood flupirtine-insensitive mechanism. Aim-2 will stringently test the role of oscillation in maintaining retinofugal projections by genetically manipulating Cx36 gene including inducible inactivation in adult animals after photoreceptor degeneration. In order to understand whether retinal oscillation has other functions, it is necessary to know which retinal neurons oscillate and through what mechanisms. Aim-3 will thus survey synaptic inputs onto genetically identifiable RGCs in two retinal deafferentation mouse models and test the hypotheses that mouse RGCs are more diverse than currently appreciated and that group-specific circuit connection characteristics exist to drive RGCs' unique physiological light responses in different groups. A fruitful outcome will in the short-term generate a resource that contains many genetically identifiable RGC types in mouse and in the long-term assign group-specific morphometric features, intrinsic membrane properties, and light response characteristics to them. These efforts fill knowledge gaps, confer a biological function to retinal oscillation in maintaining RGC central projection, and provide a strong foundation for future inquiries into retinal disease mechanisms and treatment window and/or options.

该应用的长期目标是阐明内部视网膜的机制和功能 视觉系统的开发和维护中的振荡。该提议基于存在 成人视网膜中两个独立的振荡机制。我们假设这些振荡 机制是视网膜的内置功能，被光感受器释放的谷氨酸掩盖在正常状态下 情况，但在剥离条件下（如光感受器变性和完整）中出现 先天性固定的夜间失明，以确保眼睛与大脑之间的稳定联系。我们有 发现删除连接蛋白36（CX36）但CX45基因不能沉默视网膜振荡。我们也有 初步测试了具有感光受体变性的小鼠，但没有CX36表达，发现 视网膜生成的投影变得异常。由于视网膜振荡似乎具有生物学 功能，重要的是要了解两种机制的机理细节。 AIM-1因此将重点放在 描述较少理解的夹式无敏感机制的细胞起源。 AIM-2将 严格测试振荡通过遗传操纵来维持视网膜投影的作用 CX36基因包括感光受体变性后成年动物的诱导失活。为了 了解视网膜振荡是否具有其他功能，有必要知道哪个视网膜神经元 振荡和通过什么机制。因此，AIM-3将在基因上调查突触输入 在两个视网膜脱落鼠标模型中可识别的RGC，并测试鼠标RGCS的假设 比目前所欣赏的要多样化，并且存在特定组的电路连接特性 在不同组中推动RGC的独特生理光反应。在 短期生成一种资源，该资源包含鼠标中的许多遗传识别RGC类型 长期分配特定组的形态特征，固有膜特性和光响应 他们的特征。这些努力填补了知识空白，赋予视网膜生物学功能 维持RGC中央预测的振荡，并为将来的查询提供了良好的基础 进入视网膜疾病机制和治疗窗口和/或选择。