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）：本研究的长期目标是揭示视觉系统中神经元-神经胶质相互作用的功能和机制。由于以往对视觉的研究大多集中在视觉转导级联和神经元回路上，我们对神经胶质细胞在视觉信号传导中的作用的认识仍然非常有限。有趣的是，在哺乳动物和苍蝇的眼睛中，神经胶质细胞表达视觉中间神经元的神经递质受体。目前尚不清楚胶质细胞是否直接与这些神经元沟通以调节视觉信号。在我们对果蝇视觉的初步研究中，我们发现视觉上皮胶质细胞可能在“神经节”中集中谷氨酸门控氯通道葡萄糖，神经节是一种特殊的胶质膜结构，通常介于谷氨酸能神经元间无突细胞和它的突触后伴侣T1细胞之间。当无毛细胞谷氨酸释放被阻断时，光响应结束时光感受器复极速度明显降低。重要的是，这种视觉缺陷是通过在上皮胶质细胞中特异性地降低葡萄糖表达来表型的，并且在节节结构受损的ADAM蛋白突变中也观察到。基于这些观察，我们提出存在一个光感受器-无毛细胞-上皮胶质-光感受器反馈回路，其功能是加强光感受器复极化的速度，因此对视觉的时间分辨率很重要。结合分子和细胞生物学、遗传学、组织学和电生理学的方法，我们建议进一步研究视觉上皮胶质细胞的这种新功能。具体来说，我们将1。验证层状上皮胶质细胞通过谷氨酸门控氯通道葡萄糖接受神经元输入的假设；2. 验证一种ADAM蛋白MMD需要在节节结构中定位葡萄糖以实现神经元-胶质细胞信号传导的假设；3. 确定上皮胶质细胞介导的光感受器调节机制。这些研究不仅对视觉生物学有重要意义，而且将有助于我们的视觉生物学研究