The role of glial cells in the development and function of retinal circuits

神经胶质细胞在视网膜回路发育和功能中的作用

• 批准号: 8685013
• 负责人: Georgeann Stoddard Sack
• 金额: $ 4.38万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-12-01 至 2014-09-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8685013
• 关键词: Adult; Affect; Alzheimer' s Disease; Back; Binding; Birth; Blood Vessels; Calcium; Calcium Signaling; Cells; Cellular Morphology; Dependovirus; Development; Diffuse; Epilepsy; Exhibits; Extracellular Space; Eye; Fluorescence; Fluorescence Resonance Energy Transfer; Frequencies; Ganglia; Glutamate Receptor; Glutamate Transporter; Glutamates; Health; Human; Image; Inner Nuclear Layer; Inner Plexiform Layer; Investigation; Lead; Light; Maintenance; Mediating; Membrane; Metabolism; Methods; Migraine; Molecular; Monitor; Morphology; Mus; Nervous system structure; Neural Retina; Neuroglia; Neurons; Neurotransmitters; Optics; Play; Population; Preparation; Process; Proliferating; Regulation; Research; Retina; Retinal; Role; Schizophrenia; Sensory; Signal Transduction; Slice; Surface; Synaptic Cleft; Synaptic Transmission; System; Testing; Tissues; Transgenic Mice; Vision; Visual; base; calcium indicator; cell type; clinically significant; experience; insight; neural circuit; neuron development; neurotransmitter uptake; optical sensor; prevent; programs; public health relevance; relating to nervous system; response; sensor; two-photon; uptake; visual process; visual processing; visual stimulus

DESCRIPTION (provided by applicant): Mounting evidence suggests that neurons and glia engage in bi-directional signaling that affects the function and development of neural circuits. Glia can influence the excitability of neurons, by controlling the amount of neurotransmitters in the extrasynaptic space, and can directly modulate synaptic transmission. In addition, glia are the central regulators of the neurovascular interactions that control neuronal metabolism. To better understand glial function, it is essential to unravel how the close interaction between neurons and glia is established during development and the effect this has on the stabilization of neural circuits. This proposal describes an approach to elucidate the role of neuron-glia signaling in the development of murine retinal circuits. The proposed investigations will provide the basis for a long-term research program dedicated to exploring how the precise signaling between neurons, glia, and blood vessels is established and maintained. M¿ller glia are the last cell type to proliferate in the retina, and must integrate into an existing immature circuit duringa period of spontaneous correlated activity called retinal waves. Shortly before eye opening, retinal waves are mediated by glutamatergic signaling and are thought to propagate by glutamate spillover into the extrasynaptic space. M¿ller cells mature in morphology and function during glutamatergic waves, and may stabilize retinal circuits when waves cease and vision begins. Two forms of neuron-glia signaling are explored in this proposal. In the first aim, we will determine how the maturation of glial cell transporter function affects the development of neuronal circuits. In the second aim, we will investigate how spontaneous and evoked neuronal activity influences glial calcium signaling. In aim 1 we will use optical and electrophysiological methods to describe the maturation of M¿ller cell transporter function. Levels of glutamate can be directly observed with glutamate optical sensors that increase in fluorescence when glutamate binds. I will use these sensors to monitor extrasynaptic glutamate during the transition from retinal waves to vision, and to ascertain whether or not glutamate spillover reaches M¿ller cells. M¿ller transporters will be blocked pharmacologically and two-photon calcium imaging of neuronal populations will be used to assess the effect on retinal circuits. In aim 2 we will use transgenic mice expressing the calcium indicator GCaMP3 in M¿ller cells to investigate whether neural activity drives M¿ller calcium transients throughout retinal development. An understanding of how glial cells change neuronal function as they integrate into maturing circuits will lead to fundamental insights about the cellular and molecular mechanisms of neuron-glia signaling. The maintenance of neuron-glia interactions is vital for the health of the nervous system, and in particular, the glial transporter function has proven clinical significance.

描述（由适用提供）：越来越多的证据表明，神经元和神经胶质进行双向信号传导，影响神经电路的功能和发育。神经胶质可以通过控制外斜外空间中神经递质的量来影响神经元的兴奋，并可以直接调节突触传播。另外，神经胶质是控制神经元代谢的神经血管相互作用的中心调节剂。为了更好地理解神经胶质功能，必须揭示在发育过程中如何建立神经元与胶质之间的密切相互作用以及对神经元稳定的影响。该提案描述了一种阐明神经元 - 基因信号传导在鼠永久性电路发展中的作用的方法。拟议的研究将为长期研究计划提供基础，该计划致力于探索神经元，神经胶质和血管之间的精确信号传导如何建立和维护。麦芽胶质神经胶质是在视网膜中增殖的最后一种细胞类型，必须在称为视网膜波的赞助相关活性期间集成到现有的不成熟电路中。开眼界前不久，视网膜波是由谷氨酸能信号传导介导的，并被认为可以通过谷氨酸能的Spilover传播到外突触间空间。麦芽细胞在谷氨酸能波过程中成熟的形态和功能成熟，并且当波开始停止和视力开始时，可​​能会稳定视网膜电路。在此提案中探索了两种形式的神经元 - 胶质信号传导。在第一个目标中，我们将 确定神经胶质细胞转运蛋白功能的成熟如何影响神经元电路的发展。在第二个目标中，我们将研究赞助商和唤起神经元活动如何影响神经胶质钙信号传导。在AIM 1中，我们将使用光学和电生理方法来描述M ller细胞转运蛋白功能的成熟。可以用谷氨酸光传感器直接观察谷氨酸水平，当谷氨酸结合时荧光增加。我将使用这些传感器在从视网膜波到视觉的过渡过程中监测外斜肌外谷氨酸，并确定谷氨酸Spilover是否到达M ller细胞。 M ller转运蛋白将在药理学上被阻断，并将使用神经元种群的两光子钙成像来评估对视网膜电路的影响。在AIM 2中，我们将使用表达钙指示剂GCAMP3的转基因小鼠研究神经活动是否在整个永久发育过程中驱动M ller钙瞬变。对神经胶质细胞在整合到成熟电路中的神经元功能的理解将导致有关神经元-GLIA信号传导的细胞和分子机制的基本见解。神经元相互作用的维持对于神经系统的健康至关重要，特别是，神经胶质转运蛋白功能已证明是临床的 意义。