Dynamic modulation of retinal ribbon-type synapses

视网膜带状突触的动态调制

基本信息

批准号：
7383768
负责人：
HENRIQUE Prado VON GERSDORFF
金额：
$ 33.96万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-05-01 至 2012-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7383768
关键词：
AMPA Receptors ATP phosphohydrolase Acidity Affect Affinity Amacrine Cells Animals Biochemical Biological Assay Brain Carrier Proteins Cells Chloride Channels Chloride Ion Chlorides Chromosome Pairing Computer Simulation Condition Coupling Cytosol Data Devices Electric Capacitance Electrophysiology (science)Endocytosis Excision Exocytosis Feedback Funding Future GABA Receptor GABA transporter Glutamate Transporter Glutamates Goldfish In Situ Indium Inner Plexiform Layer Kinetics Lead Life Light Localized Measurement Measures Mediating Membrane Membrane Potentials Mental Depression Modeling Monitor Morphology Nerve Neurons Output Pattern Photoreceptors Presynaptic Receptors Presynaptic Terminals Process Property Prosthesis Protons Pump Range Rate Recovery Recycling Research Research Personnel Residual state Resolution Retina Retinal Retinal Diseases Role Signal Pathway Slice Synapses Synaptic Cleft Synaptic Transmission Synaptic Vesicles Techniques Testing Thinking Time Vesicle Vision Visual Visually Impaired Persons Work channel blockers computerized data processing desensitization design gamma-Aminobutyric Acid ganglion cell insight neurotransmitter release pH gradient patch clamp postsynaptic presynaptic programs receptor research study retinal prosthesis ribbon synapse size synaptic depression time use visual information

项目摘要

DESCRIPTION: The retina detects and transmits large amounts of visual information quickly and reliably. Ribbon synapses are key components of the vertebrate retinal circuitry, forming the first and second presynaptic elements in the signaling pathway to the brain. The specialized morphology and function of the ribbons presumably endows them with a unique capacity for copious and fast neurotransmitter release, which is thought to be essential for the efficient processing and encoding of visual information. Nevertheless, the underlying cellular mechanisms that modulate and maintain transmitter output from ribbon synapses under vastly different ambient light conditions are poorly understood. Due to their large size, we are able to patch-clamp single goldfish bipolar cell terminals. This allows us to measure both presynaptic Ca currents and evoked changes in membrane capacitance that assay synaptic vesicle exocytosis and endocytosis in real time from a living nerve terminal. We have found that the reciprocal synapse of bipolar cells undergoes short-term synaptic depression. We will determine the underlying mechanisms responsible for this depression. The first hypothesis to be tested is that synaptic vesicle pool depletion at GABAergic amacrine cells, and desensitization of GABAA and AMPA receptors, contribute to depression and largely determine the recovery rate. We also find that bipolar cell terminals have a tonic inhibitory current mediated by high affinity GABAC receptors that do not desensitize. Thus the second hypothesis is that different subtypes GABA transporters in amacrine cells set the level of this tonic inhibitory current. We also have preliminary evidence that the acidity of synaptic vesicles and the process of filling synaptic vesicles with glutamate may involve chloride channels on the vesicle membrane. Biochemical studies of this process are controversial and few studies have been done in intact nerve terminals. We will thus study this process in the bipolar cell terminal embedded in a retinal slice. These studies should increase our basic understanding of signal processing in the retina and they may be relevant to retinal diseases that degenerate photoreceptors, but spare ganglion cells. A prosthetic device that stimulates the remaining neurons might restore some sight to blind people. However, this stimulation has to encode visual information at the same high rates that bipolar cells do in normal retinas. A better understanding of how bipolar cells release glutamate to excite ganglion cells will thus lead to insights on how to develop a retinal prosthesis using more physiologically relevant patterns of stimulation that match more closely the original information rates of bipolar cells. Our studies will thus hopefully aid in the future design of more efficient retinal prosthesis devices.

描述：视网膜快速可靠地检测并传输大量视觉信息。带状突触是脊椎动物视网膜电路的关键组成部分，形成大脑信号传导通路中的第一和第二突触前元件。丝带的特殊形态和功能可能赋予它们大量和快速释放神经递质的独特能力，这被认为对于视觉信息的有效处理和编码至关重要。然而，人们对在截然不同的环境光条件下调节和维持带状突触发射器输出的基本细胞机制知之甚少。由于其尺寸较大，我们能够对单个金鱼双极细胞端子进行膜片钳。这使我们能够测量突触前 Ca 电流和膜电容诱发的变化，从而实时分析活体神经末梢的突触小泡胞吐作用和内吞作用。我们发现双极细胞的相互突触会经历短期突触抑制。我们将确定造成这种萧条的根本机制。第一个要测试的假设是 GABA 能无长突细胞的突触小泡池耗尽以及 GABAA 和 AMPA 受体脱敏，导致抑郁症并在很大程度上决定恢复率。我们还发现双极细胞末梢具有由高亲和力 GABAC 受体介导的强直抑制电流，该电流不会脱敏。因此，第二个假设是无长突细胞中不同亚型的 GABA 转运蛋白决定了这种强直抑制电流的水平。我们还有初步证据表明，突触小泡的酸性以及用谷氨酸填充突触小泡的过程可能涉及囊泡膜上的氯离子通道。这一过程的生化研究存在争议，并且很少有针对完整神经末梢的研究。因此，我们将在嵌入视网膜切片的双极细胞终端中研究这一过程。这些研究应该增加我们对视网膜信号处理的基本了解，它们可能与光感受器退化但神经节细胞不受影响的视网膜疾病有关。刺激剩余神经元的假肢装置可能会让盲人恢复部分视力。然而，这种刺激必须以与正常视网膜中双极细胞相同的高速率编码视觉信息。因此，更好地了解双极细胞如何释放谷氨酸来刺激神经节细胞，将有助于深入了解如何使用与双极细胞的原始信息速率更匹配的生理相关刺激模式来开发视网膜假体。因此，我们的研究有望有助于未来设计更高效的视网膜假体装置。