Regulation of Photoreceptor Neurotransmission

感光神经传递的调节

• 批准号: 8306863
• 负责人: WALLACE B THORESON
• 金额: $ 35.28万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-06-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8306863
• 关键词: Affinity; Binding; Blindness; Buffers; Dihydropyridines; Distant; Dyes; Event; Eye; Eye diseases; Glutamates; Hair Cells; Health; Individual; Lasers; Lead; Light; Lighting; Measures; Mediating; Membrane; Membrane Potentials; Mental Depression; Metabolism; Microscopy; Mutation; Neurons; Peptides; Photoreceptors; Physiologic pulse; Physiology; Probability; Prosthesis; Proteins; Recovery; Regulation; Retina; Retinal; Retinal Cone; Shapes; Signal Transduction; Site; Stimulus; Synapses; Synaptic Cleft; Synaptic Transmission; Synaptic Vesicles; Testing; Time; Vesicle; Vision; Visual; alpha ketoglutarate; dihydropyridine; flash photolysis; fluorophore; neurotransmission; neurotransmitter release; research study; response; retinal progenitor cell; retinal rods; ribbon synapse; therapy design; visual process; visual processing; voltage

DESCRIPTION (provided by applicant): Photoreceptors transmit their light responses across the first synapse in the retina by regulating the continuous release of glutamate-containing vesicles. The mechanisms by which light-evoked changes in membrane potential regulate synaptic transmission from photoreceptors are not well understood. We propose experiments to analyze the biophysical mechanisms of release from photoreceptors. Synaptic release from photoreceptors involves both fast transient and slow sustained components of release. Sustained release is important for shaping post-synaptic responses to slow changes in illumination and transient release contributes more to responses at abrupt light offset. In Aim 1, we test whether sustained and transient components of release are both due to release from the synaptic ribbon or whether non-ribbon synaptic release sites are also involved. In Aim 2, we determine how voltage-dependent changes in release probability, the size of the releasable pool of vesicles, and the rate of vesicle replenishment interact to shape sustained and transient post-synaptic responses to light and dark at the cone synapse. In Aim 3, we test whether quantal synaptic currents evoked by release of individual synaptic vesicles are regulated by changes in cytosolic glutamate levels at the cone synapse. Understanding the mechanisms of synaptic release from photoreceptors is important for understanding basic mechanisms of vision and how vision is disrupted by mutations in synaptic proteins or mis-regulation of glutamate release. Understanding normal retinal physiology is also important for designing therapies to restore normal retinal function to diseased eyes using retinal stem cells or prosthetic devices. PUBLIC HEALTH RELEVANCE: This project studies the mechanisms by which visual signals are transmitted to downstream neurons at the first synapse in the retina. In addition to providing a better understanding of early visual processing by the retina, understanding the mechanisms by which rod and cone photoreceptors release the neurotransmitter glutamate is necessary to understand how mutations in synaptic proteins or mis-regulation of glutamate release lead to eye disease and vision loss. An understanding of normal retinal physiology is also needed for restoring vision to diseased eyes by the use of retinal stem cells, prosthetic devices, or other means.

描述（由申请人提供）：光感受器通过调节含谷氨酸的囊泡的连续释放，将其光响应传递到视网膜中的第一个突触。光引起的膜电位变化调节光感受器突触传递的机制尚不清楚。我们提出实验来分析光感受器释放的生物物理机制。光感受器的突触释放涉及快速瞬时释放和缓慢持续释放。持续释放对于塑造突触后对光照缓慢变化的反应很重要，而瞬时释放对突然光偏移的反应贡献更大。在目标 1 中，我们测试释放的持续和瞬时成分是否都是由突触带释放引起的，或者是否也涉及非带状突触释放位点。在目标 2 中，我们确定释放概率、可释放囊泡池的大小以及囊泡补充速率的电压依赖性变化如何相互作用，以形成锥体突触对光和暗的持续和瞬时突触后反应。在目标 3 中，我们测试了单个突触小泡释放引起的量子突触电流是否受到锥体突触胞质谷氨酸水平变化的调节。了解光感受器突触释放的机制对于理解视觉的基本机制以及突触蛋白突变或谷氨酸释放的错误调节如何破坏视觉非常重要。了解正常的视网膜生理学对于设计使用视网膜干细胞或假体装置恢复患病眼睛的正常视网膜功能的疗法也很重要。公共健康相关性：该项目研究视觉信号传输到视网膜第一个突触下游神经元的机制。除了更好地了解视网膜的早期视觉处理之外，了解视杆细胞和视锥细胞光感受器释放神经递质谷氨酸的机制对于了解突触蛋白突变或谷氨酸释放的错误调节如何导致眼部疾病和视力丧失是必要的。通过使用视网膜干细胞、假体装置或其他方式恢复患病眼睛的视力还需要了解正常的视网膜生理学。