Synaptic Transmission in the Rod Pathway of the Mammalian Retina

描述（由申请人提供）：在哺乳动物视网膜内，AII无长突细胞定位成在产生视网膜输出的大多数平行通路内的视杆细胞和视锥细胞介导的视觉期间起作用。因此，理解AII对于理解内层视网膜内的信号传导至关重要。该建议包括两个具体的目标，这将产生对AIIs的突触输入的调节和在正常和退化的视网膜中塑造AIIs输出的机制的洞察。具体目标1测试RB-AII突触在视杆介导的视觉信号传导中起双重作用的假设：在RB通路是传递视杆输出的唯一手段的条件下，突触充当事件检测器;在足以允许视杆介导的信号通过视杆-视锥间隙连接进入视锥通路的光强度下，突触充当平均亮度的指示器。具体目标2测试的假设，改变K通道功能产生异常振荡活动的AII的rd 1小鼠视网膜，模型的研究人类视网膜色素变性（RP）。与公共卫生的相关性：视网膜色素变性（RP），影响全球约1/4，000 - 5，000的个体（仅在美国就有100，000例患者），是指一系列视网膜疾病，其中光感受器死亡（视杆细胞，然后是视锥细胞）。rd 1小鼠是一种已建立的人RP模型，在其视网膜输出中表现出异常的模式化活性。我们的初步工作是拟议工作的基础，表明这种活动是由细胞变化引起的。因此，拟议研究的结果将提供有关感光细胞变性后视网膜内回路如何变化的新信息，并可能提供对治疗的见解，这些治疗将防止等待致盲疾病治疗的患者视觉系统的活动依赖性变化。该项目的目的是解决国家眼科和视力研究计划中视网膜疾病计划的三个明确目标：1）确定治疗视网膜色素变性的潜在治疗策略，2）增加对视网膜色素变性的了解， 感光后适应（即，神经回路中的增益控制），以及3）增加对神经网络内的视网膜细胞相互作用如何产生可解释为视觉图像的信号的理解。 公共卫生相关性：在哺乳动物的视网膜中，来自光感受器（视杆细胞和视锥细胞）的信号被分配到一系列并行的神经回路，这些神经回路为神经节细胞（GC）提供输入。有多种GC“类型”（~15-20）;每种类型编码视觉场景的不同方面（例如，亮度、运动等）。为了理解视觉世界是如何编码为神经信号的，那么，必须了解这些视网膜回路的功能。它有 很明显，一种单一类型的视网膜神经元，AII无长突细胞，通过大多数这些平行通路参与信号传导。因此，理解AII对于理解视网膜内的信号传导至关重要。该建议包括两个具体的目标，这将产生对AIIs的突触输入的调节和在正常和退化的视网膜中塑造AIIs输出的机制的洞察。

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.