Mechanisms of feedback from retinal horizontal to cone cells

视网膜水平到视锥细胞的反馈机制

• 批准号: 8126524
• 负责人: Tzu-Ming Wang
• 金额: $ 5.3万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-17 至 2014-05-16
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8126524
• 关键词: AMPA Receptors; Acidity; Address; Agonist; Attenuated; Calcium; Calcium Channel; Detection; Feedback; Fishes; Fluorescence; Glutamate Receptor; Intervention; Light; Lighting; Mediating; Membrane; Monitor; PHluorin; Pattern; Photoreceptors; Physiological; Play; Prosthesis; Retina; Retinal; Retinal Cone; Role; Scientist; Signal Transduction; Surface; Synapses; Synaptic Cleft; TRPV1 gene; Testing; Transgenic Organisms; Variant; Vision; Visual; Zebrafish; computerized data processing; design; gene therapy; horizontal cell; neurotransmitter release; overexpression; receptive field; response; retinal neuron; voltage

DESCRIPTION (provided by applicant): Photoreceptors not only receive light as an input, they also get feedback signals from horizontal cells (HCs). Negative feedback from HCs is believed to be the fundamental mechanism underlying the center-surround organization of the receptive field of retinal neurons. The mechanism responsible for HC feedback is controversial, but one major hypothesis is that the calcium current at the cone terminal is regulated by the acidity (i.e. pH) of the synaptic cleft. Although the pH hypothesis is currently very popular, it is still unknown if the pH value of the synaptic cleft really changes under physiological conditions, and if this change is significant enough to mediate the feedback. To address these questions, transgenic zebrafish expressing a pH-sensitive GFP variant either on HC or cone surfaces have been created in order to monitor the pH within the synaptic invagination. Patterned illumination will be transmitted onto the retina while membrane fluorescence is monitored. A pH change within the cone synaptic cleft will be reflected by a corresponding change in fluorescence intensity, and the direction and magnitude of the fluorescence drift will be compared to the expected pH change required for mediating feedback responses. Recently, an unexpected positive feedback mechanism from HCs to cones was discovered, which presumably boosts the gain of photoreceptors. This positive feedback is likely initiated by calcium influx into HCs, which subsequently accelerates neurotransmitter release from cones through an unknown mechanism. To examine the importance of HC calcium influx in initiating this feedback, transgenic zebrafish expressing GluR2 in HCs have been created. Because GluR2-containing glutamate receptors are calcium-impermeable, positive feedback is expected to be attenuated. To test if calcium alone is sufficient to elicit positive feedback, transgenic zebrafish expressing TRPV1 channels in HCs will be created. TRPV1 channels are calcium- permeable, therefore, if calcium itself is sufficient to initiate positive feedback, a TRPV1 agonist should trigger the positive feedback as well. This proposal addresses long standing debates in negative feedback and provides clues for understanding the newly discovered positive feedback in visual signal processing. Understanding how feedback signals are given to cone cells will help vision scientists design better interventions, such as gene therapy or prosthetic devices, to aid in restoring vision. PUBLIC HEALTH RELEVANCE: Relevance Understanding how visual signals are processed in the retina will help vision scientists to design better interventions like gene therapy or prosthetic devices for restoring vision.

描述（由申请人提供）：光感受器不仅接收光作为输入，还从水平细胞（HCS）中获得反馈信号。 HCS的负反馈被认为是视网膜神经元接受场中心围绕组织的基本机制。负责HC反馈的机制是有争议的，但一个主要的假设是，锥末端的钙电流受突触裂口的酸度（即pH）调节。尽管pH假设目前非常流行，但在生理条件下，突触裂口的pH值是否确实发生了变化，并且这种变化是否足以介导反馈。为了解决这些问题，已经创建了在HC或锥体表面上表达pH敏感GFP变体的转基因斑马鱼，以监视突触间隔内的pH值。在监测膜荧光的同时，将图案化的照明传输到视网膜上。圆锥突触裂缝内的pH变化将由荧光强度的相应变化反映，并且将荧光漂移的方向和幅度与中介反馈反应所需的预期pH变化进行比较。最近，发现了从HCS到锥体的意外阳性反馈机制，这大概可以增强感光体的增益。这种积极的反馈很可能是由钙涌入HC的，随后通过未知机制加速了神经递质从锥体释放。为了检查HC钙涌入在启动此反馈中的重要性，已经创建了HC中的转基因斑马鱼表达Glur2。由于含GLUR2的谷氨酸受体是可钙化的，因此预计阳性反馈将被减弱。为了测试单独的钙是否足以引起阳性反馈，将创建HCS中的转基因斑马鱼表达TRPV1通道。因此，TRPV1通道是钙渗透的，因此，如果钙本身足以引发正反馈，则TRPV1激动剂也应触发正反馈。该提案解决了负面反馈中的长期辩论，并提供了了解新发现的视觉信号处理中新发现的积极反馈的线索。了解如何发出对锥细胞的反馈信号将帮助视力科学家设计更好的干预措施，例如基因治疗或假肢设备，以帮助恢复视力。 公共卫生相关性：相关性了解视网膜中如何处理视觉信号将帮助视力科学家设计更好的干预措施，例如基因疗法或假肢设备来恢复视力。