Regulation of Photoreceptor Neurotransmission

感光神经传递的调节

• 批准号: 7922815
• 负责人: WALLACE B THORESON
• 金额: $ 9.01万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2010-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7922815
• 关键词: Affinity; Binding; Blindness; Buffers; Dihydropyridines; Distant; Dyes; Event; Eye; Eye diseases; Glutamates; Hair Cells; Individual; Lasers; Lead; Light; Lighting; Measures; Mediating; Membrane; Membrane Potentials; 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; Vertebrate Photoreceptors; Vesicle; Vision; Visual; alpha ketoglutarate; depression; dihydropyridine; flash photolysis; fluorophore; neurotransmission; neurotransmitter release; public health relevance; research study; response; retinal progenitor cell; 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囊泡的连续释放，在视网膜中的第一个突触中传递其光反应。尚不清楚膜电位调节突触传播的光诱发变化的机制尚不清楚。我们提出了实验，以分析从感光体释放的生物物理机制。从光感受器中释放突触释放涉及快速瞬态和缓慢持续的释放组成部分。持续释放对于塑造突触后的响应对缓慢的照明变化和瞬态释放的响应很重要，并且在突然的光偏移下对响应有更多的贡献。在AIM 1中，我们测试释放的持续和瞬态释放成分是否既是从突触色带中释放出来的，否则是否还涉及非rib骨突触释放位点。在AIM 2中，我们确定了释放概率，可释放的囊泡池的大小以及囊泡补给的速率如何相互作用，以形成圆锥体突触时对光和黑暗的持续和短暂的突触后反应相互作用。在AIM 3中，我们测试通过释放单个突触囊泡引起的量子突触电流是否受锥突触处的胞质谷氨酸水平的变化来调节。了解从光感受器中释放突触的机制对于理解视觉的基本机制以及视力如何被突触蛋白中突变或谷氨酸释放的错误调节所破坏。了解正常的视网膜生理对于设计疗法，使用视网膜干细胞或人固定装置恢复患病的眼睛的正常视网膜功能也很重要。公共卫生相关性：该项目研究了视觉信号在视网膜第一次突触中传播到下游神经元的机制。除了提供视网膜对早期视觉处理的更好理解外，还要了解杆和锥形光感受器释放神经递质谷氨酸的机制，对于了解突触蛋白中突触中的突变或谷氨酸释放的不调节如何导致眼部疾病和视力丧失。还需要了解正常的视网膜生理学，以通过使用视网膜干细胞，假肢设备或其他手段来恢复视力以使眼睛的眼睛恢复。