Development and Dynamics of Transmission at Mammalian Rod Bipolar Cell Synapses

哺乳动物杆状双极细胞突触的发育和传递动力学

• 批准号: 7749376
• 负责人: TIM M JARSKY
• 金额: $ 5.17万
• 依托单位: NORTHWESTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7749376
• 关键词: Address; Amacrine Cells; Animal Model; Biological Assay; Cells; Cessation of life; Characteristics; Coupled; Darkness; Development; Exocytosis; Experimental Models; Eye; Glutamates; Goals; In Vitro; Mus; Natural regeneration; Neurons; Pathology; Pathway interactions; Phenotype; Photoreceptors; Preparation; Presynaptic Terminals; Process; Property; Public Health; Research; Research Personnel; Retina; Retinal; Retinitis Pigmentosa; Signal Transduction; Slice; Synapses; Synaptic Transmission; Training; Universities; Vertebrate Photoreceptors; Vesicle; Vision; Visual; Work; career; dark rearing; design; information processing; mouse model; neural circuit; photoreceptor degeneration; postnatal; postsynaptic; presynaptic; research study; retinal neuron; retinal rods; transmission process; visual information; voltage clamp

DESCRIPTION (provided by applicant): My career goal is to study information processing in the retina as an independent investigator at a research university. The project proposed here will provide me with the training necessary to accomplish this goal. Specifically, the proposed work will address two specific aims using the rod bipolar pathway of the mouse retina as an experimental model. One: how does transmission at the rod bipolar-All amacrine cell synapse of the mammalian retina develop? Two: when deprived of visual input, resulting either from dark- rearing or from rod degeneration in a mouse model of retinitis pigmentosa, does the rod bipolar-All synapse behave as an immature synapse, as a mature synapse, or as something different? The answer to this second question has significant implications for treatment of retinal pathologies arising from photoreceptor degeneration such as that occurring in retinitis pigmentosa. It is important to establish the functional properties of inner retinal synapses and to determine whether these synapses are capable of transferring visual signals before attempting to restore vision by replacement or regeneration of photoreceptors. Experiments designed to achieve these specific aims will be performed in an in vitro slice preparation of murine retina. Rod bipolar and All amacrine cells will be visualized and paired voltage-clamp recordings will be made from synaptically coupled neurons. Depolarization of the presynaptic rod bipolar will elicit Ca^* into its axon terminal, and this Ca^* influx will be recorded as a Ca current. Ca^* influx will evoke exocytosis of glutamatergic vesicles from the terminal; excitatory postsynaptic currents recorded in the All amacrine will allow me to assay this exocytosis. Relevance to public health: Many retinal pathologies cause photoreceptor (rod and cone) death, which deprives retinal neurons of their normal inputs and results in changes in the synaptic connections between them. Because tremendous efforts are being made to regenerate photoreceptors to treat or cure retinal pathologies, it is critical to understand the extent to which the neural circuitry of the diseased retina is capable of processing visual information. The work proposed here will examine a well-characterized retinal synapse to determine the normal course of the development of synaptic transmission and to understand how synaptic transmission following photoreceptor degeneration compares to that in the developing retina.

描述(由申请人提供)：我的职业目标是作为一名研究型大学的独立研究员研究视网膜的信息处理。这里提出的项目将为我提供实现这一目标所需的培训。具体地说，拟议的工作将解决两个特定的目标，使用小鼠视网膜的视杆双极通路作为实验模型。一：哺乳动物视网膜的视杆双极-所有无长突细胞突触的传输是如何发展的？第二：在视网膜色素变性的小鼠模型中，当视觉输入被剥夺时，无论是黑暗饲养还是视杆变性，视杆双极突触是表现为不成熟的突触，成熟的突触，还是不同的突触？第二个问题的答案对治疗由感光细胞变性引起的视网膜病变具有重要意义，例如发生在视网膜色素变性的视网膜病变。在试图通过替换或再生光感受器恢复视力之前，重要的是要确定视网膜内部突触的功能特性，并确定这些突触是否能够传递视觉信号。为实现这些特定目标而设计的实验将在小鼠视网膜的体外切片制备中进行。视杆细胞、双极细胞和所有无长突细胞将被可视化，并且将由突触耦合神经元进行成对的电压钳记录。突触前杆双极的去极化将引起Ca^*进入其轴突终末，这种Ca^*内流将被记录为钙电流。Ca^*内流将引起谷氨酸能小泡从终末的胞吐作用；在All-amacine中记录的兴奋性突触后电流将使我能够检测这种胞吐作用。与公众健康相关：许多视网膜病变导致光感受器(视杆细胞和视锥细胞)死亡，这剥夺了视网膜神经元的正常输入，并导致它们之间的突触连接发生变化。由于人们正在做出巨大的努力来再生光感受器来治疗或治愈视网膜疾病，因此了解疾病视网膜的神经电路能够处理视觉信息的程度是至关重要的。本文提出的工作将研究一个具有良好特征的视网膜突触，以确定突触传递的正常过程，并了解光感受器退化后的突触传递与发育中的视网膜相比如何。