Synaptic Transmission in the Rod Pathway of the Mammalian Retina

描述（由申请人提供）：在哺乳动物视网膜中，AII无突细胞被定位在产生视网膜输出的大多数平行通路中，在杆状和锥体介导的视觉过程中发挥作用。因此，理解AII对于理解视网膜内部的信号传导至关重要。该提案包括两个具体目标，将产生对aii突触输入的调节以及在正常和退化视网膜中形成aii输出的机制的见解。特异性目的1验证了RB - AII突触在杆状细胞介导的视觉信号传导中起双重作用的假设：在RB通路是传递杆状细胞输出的唯一途径的情况下，突触充当事件检测器；当光强度足以使杆状细胞介导的信号通过杆状细胞-锥体间隙连接进入锥体通路时，突触可作为平均亮度的指示器。特异性Aim 2验证了改变的K通道功能在rd1小鼠视网膜aii中产生异常振荡活动的假设，rd1小鼠视网膜是研究人类视网膜色素变性（RP）的模型。与公共卫生相关：视网膜色素变性（RP），影响全球约4000 - 5000人中的1人（仅在美国就有10万名患者），是指一系列视网膜疾病，其中光感受器死亡（视杆细胞随后是视锥细胞）。rd1小鼠是人类RP的建立模型，在其视网膜输出中表现出异常的模式活动。我们的初步工作，构成了拟议工作的基础，表明这种活动是由人工智能的细胞变化引起的。因此，拟议研究的结果将提供有关视网膜内回路在光感受器变性后如何变化的新信息，并可能为治疗盲性疾病等待治疗的患者提供预防视觉系统活动依赖性变化的治疗方法。本项目旨在解决国家眼科和视觉研究计划视网膜疾病项目的三个明确目标：1)确定色素性视网膜炎治疗的潜在治疗策略，2)增加认识

DESCRIPTION (provided by applicant): Within the mammalian retina, the AII amacrine cell is positioned to function during both rod- and cone-mediated vision within most of the parallel pathways that generate retinal output. Therefore, understanding the AII is a critical to comprehending signaling within the inner retina. This proposal comprises two specific aims that will generate insight into the regulation of synaptic input to AIIs and the mechanisms shaping AIIs' outputs both in the normal and in the degenerating retina. Specific Aim 1 tests the hypothesis that RB - AII synapse serves a dual purpose in rod-mediated visual signaling: under conditions in which the RB pathway is the only means of conveying rod output, the synapse serves as an event detector; at light intensities sufficient to permit rod-mediated signals pass into the cone pathway via rod-cone gap junctions, the synapse serves as an indicator of mean luminance. Specific Aim 2 tests the hypothesis that altered K channel function generates aberrant oscillatory activity in AIIs of the rd1 mouse retina, a model for the study of human retinitis pigmentosa (RP). Relevance to Public Health: Retinitis pigmentosa (RP), which affects approximately 1 in 4,000 - 5,000 individuals worldwide (and 100,000 patients in the US alone), refers to a collection of retinal diseases in which photoreceptors die (rods followed by cones). The rd1 mouse is an established model of human RP and exhibits aberrant patterned activity in its retinal output. Our preliminary work, which forms the foundation for the proposed work, demonstrates that this activity arises from cellular changes to AIIs specifically. Therefore, the results arising from the proposed studies will provide new information about how the inner retinal circuitry changes following photoreceptor degeneration and may provide insight into treatments that will prevent activity-dependent changes in the visual systems of patients awaiting treatment for blinding diseases. The aims of this project address three explicit goals of the Retinal Diseases Program in the National Plan for Eye and Vision Research: 1) determining potential therapeutic strategies for treatment of retinitis pigmentosa, 2) increasing understanding of post-photoreceptor adaptation (i.e., gain control in neural circuits), and 3) Increasing understanding of how retinal cellular interactions within neural networks generate signals that are interpretable as visual images. PUBLIC HEALTH RELEVANCE: In the mammalian retina, signals arising from photoreceptors--rods and cones--are distributed to a series of parallel neural circuits that provide input to ganglion cells (GCs). There are multiple GC 'types' (~15-20); each type encodes a different aspect of the visual scene (e.g., luminance, motion, etc.). To understand how the visual world is encoded as a neural signal, then, the function of these retinal circuits must be understood. It has become evident that a single type of retinal neuron, the AII amacrine cell, participates in signaling through most of these parallel pathways. Therefore, understanding the AII is a critical to comprehending signaling within the retina. This proposal comprises two specific aims that will generate insight into the regulation of synaptic input to AIIs and the mechanisms shaping AIIs' outputs in both the normal and the degenerated retina.