Molecular Basis of Photoreceptor Wiring

感光器布线的分子基础

• 批准号: 10165722
• 负责人: Kirill A. Martemyanov
• 金额: $ 10.79万
• 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/10165722
• 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.

项目摘要 哺乳动物棒和锥形感受器对于视力不可或缺。他们将光转换为电气 反应，然后在视网膜电路上传播并进入大脑。电气传播 受感受器产生的信号需要它们与下游中间神经元的突触连通性， 双极细胞。已知光感受器和双极细胞之间突触通信的缺陷已知 引起人类先天性固定失明，这种状况为特征，以光敏性差和 在许多其他眼部条件下，频繁的合并症。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 更好地了解盲目条件并制定治疗策略。 两种类型的光感受器，杆和锥体形成不同类型的不同连接 双极细胞。这种突触特异性隔离视觉输入，并在设置 我们视力的基本特性，包括广泛的光敏性和对比度的动态范围 歧视。但是，负责选择性连通性的分子机制 光感受器及其下游双相神经元未知。我们已经确定了一个新的细胞粘附 - 像分子ELFN1一样，该ELFN1特别存在于光感受器突触。我们发现elfn1形成了 双极细胞中的主要神经递质受体的反式突触相互作用mglur6。破坏 ELFN1导致棒突触的选择性损失。我们假设ELFN1-MGLUR6互动播放键 在介导杆感光器的选择性突触连通性中的作用，并指导光的传播 跨视网膜电路的信号。 该假设将通过追求三个互补的特定目的来检验（i） 敲除小鼠模型和基因救援实验，以确定ELFN1功能的细胞机制 在Rod感光体和RBC之间的突触形成时，（ii）研究ELFN1在 指导跨视网膜电路的传播信号，（iii）检查分子机制 ELFN1实现其突触作用。提出解决这些目标的策略将需要协同作用 生化，分子生物学，电生理和生理方法的结合，每种 利用强大的试剂和动物模型的存在。