Molecular Basis of Photoreceptor Wiring

感光器布线的分子基础

• 批准号: 10412170
• 负责人: Kirill A. Martemyanov
• 金额: $ 10.16万
• 依托单位: SCRIPPS FLORIDA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2022-04-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10412170
• 关键词: Ablation; Address; Affect; Afferent Neurons; Animal Model; Area; Biochemical; Biological; Bipolar Neuron; Blindness; Brain; Calcium Channel; Cell Adhesion; Cells; Communication; Complex; Cone; Couples; Data; Dendrites; Detection; Development; Discrimination; Dissection; Electron Microscopy; Electrophysiology (science); Electroporation; Electroretinography; Enabling Factors; Functional disorder; Gap Junctions; Generations; Genetic; Glutamates; Goals; Heart; Human; Interneurons; Investigation; Knockout Mice; Light; Mediating; Molecular; Mus; Nervous System Physiology; Neuraxis; Neurons; Neurotransmitter Receptor; Night Blindness; Pathway interactions; Photophobia; Photoreceptors; Phototransduction; Physiological; Play; Presynaptic Terminals; Property; Proteins; Reagent; Reporter; Research; Retina; Retinal Cone; Retinal Diseases; Rod; Role; Signal Transduction; Specificity; Synapses; Synaptic Transmission; Testing; Vertebrate Photoreceptors; Virus; Vision; Visual; Visual system structure; Work; cell type; comorbidity; confocal imaging; experience; experimental study; extracellular; in vivo; innovation; loss of function; luminance; mouse model; neurotransmitter release; novel; postsynaptic; recruit; relating to nervous system; response; retinal neuron; retinal rods; segregation; selective expression; synaptic failure; synaptic function; synaptogenesis; tool; transmission process

PROJECT SUMMARY Mammalian rod and cone photoreceptors are indispensible for vision. They convert light into electrical response, which is then propagated across the retina circuit and into the brain. Transmission of the electrical signal generated by the photoreceptors requires their synaptic connectivity with the downstream interneurons, the bipolar cells. Deficits in synaptic communication between photoreceptors and bipolar cells are known to cause congenital stationary blindness in humans, a condition characterized by poor light sensitivity and frequent co-morbidity with many other ocular conditions. Our long-term goal is to elucidate molecular and cellular mechanisms by which photoreceptors establish synapses and transmit their signals with the hope to better understand blinding conditions and devising strategies for their treatment. Two types of the photoreceptors, rods and cones, form distinct connections with different types of the bipolar cells. This synaptic specificity segregates visual inputs and plays an essential role in setting up the fundamental properties of our vision, including a wide dynamic range of light sensitivity and contrast discrimination. However, the molecular mechanisms responsible for selective connectivity between photoreceptors and their downstream bipolar neurons are unknown. We have identified a new cell adhesion- like molecule ELFN1 that specifically present at the photoreceptors synapses. We found that ELFN1 forms a trans-synaptic interaction with the principal neurotransmitter receptor in bipolar cells, mGluR6. Disruption of ELFN1 results in selective loss of rod synapses. We hypothesize that ELFN1-mGluR6 interaction play key roles in mediating selective synaptic connectivity of rod photoreceptors and direct the propagation of light signal across retina circuit. This hypothesis will be tested by pursuing three complementary Specific Aims that will (i) use knockout mouse models, and genetic rescue experiments to determine cellular mechanisms of ELFN1 function in the formation of synapse between rod photoreceptors and ON-RBC, (ii) investigate the role of ELFN1 in directing the propagation light signal across retina circuitry, and (iii) examine molecular mechanisms by which ELFN1 enables its synaptogenic effects. The strategy proposed to address these aims will entail a synergistic combination of biochemical, molecular biological, electrophysiological, and physiological approaches, each exploiting the existence of a powerful array of reagents and animal models.

项目概要 哺乳动物的视杆细胞和视锥细胞感光器对于视觉来说是不可或缺的。它们将光能转化为电能 反应，然后通过视网膜回路传播到大脑。电力传输 光感受器产生的信号需要它们与下游中间神经元的突触连接， 双极细胞。已知光感受器和双极细胞之间的突触通讯缺陷 导致人类先天性静止性失明，这种疾病的特征是光敏感性差和 经常与许多其他眼部疾病并存。我们的长期目标是阐明分子和 光感受器建立突触并传输信号的细胞机制，希望 更好地了解致盲情况并制定治疗策略。 两种类型的感光细胞（视杆细胞和视锥细胞）与不同类型的感光细胞形成不同的连接。 双极细胞。这种突触特异性分离了视觉输入，并在建立视觉输入方面发挥着重要作用。 我们视觉的基本特性，包括宽动态范围的光敏感度和对比度 歧视。然而，负责选择性连接的分子机制 光感受器及其下游双极神经元尚不清楚。我们发现了一种新的细胞粘附—— 像分子 ELFN1 专门存在于光感受器突触处。我们发现 ELFN1 形成 与双极细胞中主要神经递质受体 mGluR6 的跨突触相互作用。扰乱 ELFN1 导致杆状突触选择性丧失。我们假设 ELFN1-mGluR6 相互作用发挥关键作用 在介导视杆细胞选择性突触连接和指导光传播中的作用 信号穿过视网膜电路。 该假设将通过追求三个互补的具体目标来检验，这些目标将 (i) 使用 敲除小鼠模型和基因拯救实验以确定 ELFN1 功能的细胞机制 在杆状光感受器和 ON-RBC 之间突触的形成中，(ii) 研究 ELFN1 在 引导传播光信号穿过视网膜电路，以及（iii）检查分子机制 ELFN1 能够发挥其突触作用。为实现这些目标而提出的战略将需要协同作用 生物化学、分子生物学、电生理学和生理学方法的结合，每种方法 利用现有的一系列强大的试剂和动物模型。