Neuron-glia interactions in Drosphila visual neuropiles

果蝇视觉神经桩中神经元-胶质细胞的相互作用

• 批准号: 8297861
• 负责人: HONG-SHENG LI
• 金额: $ 41.13万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8297861
• 关键词: Amacrine Cells; Astrocytes; Biological; Biology; Cells; Defect; Drosophila eye; Drosophila genus; Epithelial; Eye; Feedback; Genetic; Genetic Models; Glutamates; Goals; Interneurons; Knowledge; Light; Maintenance; Mediating; Membrane; Molecular; Neurobiology; Neuroglia; Neurons; Neurotransmitter Receptor; Neurotransmitters; Phenocopy; Photoreceptors; Phototransduction; Proteins; Regulation; Research; Resolution; Retinal Diseases; Role; Signal Transduction; Speed; Structure; Synaptic Transmission; Testing; Therapeutic; Vision; Visual; Visual system structure; base; design; fly; glutamate-gated chloride channel; knock-down; mutant; neuron development; novel; postsynaptic; prevent; response; retinal neuron

DESCRIPTION (provided by applicant): The long-term goal of the proposed research is to reveal functions and mechanisms of neuron-glia interaction in visual systems. As previous studies on vision have mostly been focused on the visual transduction cascades and the neuronal circuits, our knowledge about the role of glial cells in visual signaling is still very limited. Intriguingly, glial cells express receptors for neurotransmitters of visual interneurons i both mammalian and fly eyes. It is unknown whether glial cells directly communicate with those neurons for regulation of visual signaling. In our preliminary studies on Drosophila vision, we found that the visual epithelial glia may concentrate a glutamate-gated chloride channel GluCl in 'gnarl', a special glial membrane structure that typically interposes between a glutamatergic interneuron amacrine cell and its postsynaptic partner T1 cell. When the glutamate release from amacrine cell was blocked, the speed of photoreceptor repolarization at the end of light response was reduced significantly. Importantly, this visual defect was phenocopied by knocking down the GluCl expression specifically in the epithelial glia, and was also observed in an ADAM protein mutant of impaired gnarl structure. Based on these observations, we propose the existence of a photoreceptor-amacrine cell-epithelial glia-photoreceptor feedback loop, which functions to reinforce the speed of photoreceptor repolarization and is thus important for the temporal resolution of vision. Using a combination of molecular and cell biological, genetic, histological, and electrophysiological approaches, we propose to further investigate this novel function of visual epithelial glia. Specifically, we will 1. Test the hypothesis that laminar epithlial glia receive neuronal input through the glutamate-gated chloride channel GluCl; 2. Test the hypothesis that an ADAM protein MMD is required to localize GluCl in the gnarl structure for the neuron-glia signaling; 3. Identify the mechanism of epithelial glia-mediated photoreceptor regulation. These studies are not only important to visual biology, but will also contribute to our understanding of glial function in general. PUBLIC HEALTH RELEVANCE: Visual glia cells are essential for retinal neuron development and protection, and are implicated in a variety of retinopathies. In this proposal we plan to use the Drosophila eye as a genetic model to study how visual glia interact directly with neurons and how they reciprocally regulate the activity of each other. Findings from this study may provide valuable clues to therapeutic designs directed to prevent degeneration of retinal neurons.

描述（由申请人提供）：拟议的研究的长期目标是揭示视觉系统中神经元相互作用的功能和机制。由于先前关于视觉的研究主要集中在视觉转导级联反应和神经元电路上，因此我们对神经胶质细胞在视觉信号传导中的作用的了解仍然非常有限。有趣的是，神经胶质细胞表达视觉中间神经元的神经递质的受体，我既哺乳动物又是蝇眼。尚不清楚神经胶质细胞是否直接与那些神经元传达以调节视觉信号传导。在我们对果蝇视觉的初步研究中，我们发现视觉上皮神经胶质可能会在“ gnarl”中浓缩谷氨酸门控通道Glucl，这是一种特殊的神经胶质膜结构，通常在谷氨酸膜间膜间无链氨基木氨基氨基氨基氨基氨基链纤维膜及其后促伴侣T1细胞之间插入。当谷氨酸从团体细胞中释放时，光感受器在光反应结束时复极的速度显着降低。重要的是，通过在上皮神经胶质中特异性击倒Glucl表达来表达这种视觉缺陷，并在受损的GNARL结构的Adam蛋白突变体中观察到。基于这些观察结果，我们提出了具有感光 - 氨基氨基氨基氨基细胞上皮胶质感受器的反馈回路的存在，该反馈循环可增强光感受器的速度，因此对于视力的时间分辨率很重要。使用分子和细胞生物学，遗传学，组织学和电生理方法的结合，我们建议进一步研究视觉上皮胶质神经胶质的新功能。具体而言，我们将1。检验层状上皮神经胶质通过谷氨酸门控氯化物通道Glucl接受神经元输入的假设。 2。检验以下假设：ADAM蛋白MMD需要将Glucl定位在神经元 - 葡萄球菌信号传导的GNARL结构中； 3。确定上皮胶质介导的光感受器调节的机制。这些研究不仅对视觉生物学很重要，而且还将有助于我们 一般来说，了解神经胶质功能。 公共卫生相关性：视觉胶质细胞对于视网膜神经元发展和保护至关重要，并且与各种视网膜病有关。在此提案中，我们计划将果蝇眼作为遗传模型，以研究视觉神经胶质如何直接与神经元相互作用，以及它们如何相互调节彼此的活性。这项研究的结果可能为导致视网膜神经元变性的治疗设计提供了宝贵的线索。