Dynamic modulation of retinal ribbon-type synapses

描述：视网膜能够快速可靠地检测和传输大量的视觉信息。带状突触是脊椎动物视网膜回路的关键组成部分，构成了通向大脑的信号通路中的第一和第二突触前元件。功能区的特殊形态和功能可能赋予了它们一种独特的能力，可以大量而快速地释放神经递质，这被认为是视觉信息有效处理和编码所必需的。然而，在非常不同的环境光条件下，调节和维持带状突触的递质输出的潜在细胞机制仍然知之甚少。由于它们的体积很大，我们能够膜片钳单个金鱼双极细胞终末。这使我们能够测量突触前钙电流和膜电容的诱发变化，从而实时地从活的神经末梢分析突触小泡的胞吐和内吞作用。 我们发现双极细胞的相互突触经历了短期的突触抑制。我们将确定导致这种抑郁的潜在机制。第一个要检验的假说是，GABA能无长突细胞的突触囊泡池耗尽，以及GABA和AMPA受体的失敏，导致抑郁，并在很大程度上决定了恢复率。我们还发现，双极细胞终末有一个由不脱敏的高亲和力GABAC受体介导的紧张性抑制电流。因此，第二个假设是，无长突细胞中不同亚型的GABA转运体设定了这种紧张性抑制电流的水平。我们也有初步证据表明，突触小泡的酸性和谷氨酸填充突触小泡的过程可能涉及小泡膜上的氯离子通道。对这一过程的生化研究存在争议，对完整神经末梢的研究也很少。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。这些研究应该会增加我们对视网膜信号处理的基本了解，它们可能与视网膜疾病有关，这些疾病使光感受器退化，但保留了神经节细胞。一种刺激剩余神经元的假体装置可能会让盲人恢复一些视力。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是如何释放谷氨酸来兴奋神经节细胞的，将有助于我们深入了解如何使用更具生理相关性的刺激模式来开发视网膜假体，这些模式与双极细胞的原始信息率更接近。因此，我们的研究有望对未来设计更有效的视网膜假体设备有所帮助。

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.