Different modes of glutamate release at PF-SC synapses in the cerebellum

小脑 PF-SC 突触谷氨酸释放的不同模式

• 批准号: 8518020
• 负责人: Benjamin Nahir
• 金额: $ 5.57万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8518020
• 关键词: Action Potentials; Address; Axon; Cerebellar cortex structure; Cerebellum; Data; Electrophysiology (science); Fiber; Frequencies; Future; Generations; Glutamates; Goals; Heterogeneity; Individual; Interneurons; Knowledge; Laser Scanning Microscopy; Lasers; Lead; Light; Location; Maps; Mediating; Methods; Motor; Movement; N-Methyl-D-Aspartate Receptors; Neurons; Optics; Output; Pathology; Photons; Physiological; Postsynaptic Membrane; Process; Property; Purkinje Cells; Regulation; Relative (related person); Reporting; Research; Signal Transduction; Source; Structure; Supporting Cell; Synapses; System; Testing; Time; Training Activity; Trees; Vesicle; Work; computerized data processing; feeding; granule cell; improved; motor control; motor deficit; motor disorder; motor learning; neurotransmission; novel; novel therapeutics; postsynaptic; public health relevance; stellate cell; therapeutic target; treatment strategy; two-photon

DESCRIPTION (provided by applicant): The cerebellum is primarily responsible for coordinating motor movement by processing and modifying descending motor commands from the cortex. General cerebellar circuitry is rather homogenous; however, considerable heterogeneity exists at distinct synaptic connections within this microcircuitry. Preliminary studies suggest there is more variability in the regulation of glutamate release at individual parallel fiber terminals than originally reported. The goal of this proposal is to better understan signaling properties of the parallel fibers through a careful study of individual parallel fiber - stellate cell synapses. Aim 1 will investigate the source of glutamate responsible for activation o extrasynaptic NMDA receptors on the stellate cells. This work will identify whether action potential-dependent, synchronous release or action potential-independent, asynchronous release is the primary method of glutamate release required to elicit NMDA receptor currents. Using 2-photon laser uncaging of glutamate, Aim 2 will determine the extent of NMDAR activation by mimicking asynchronous and multivesicular release. This Aim will also establish whether the NMDARs are localized perisynaptically or dispersed evenly throughout the stellate cell dendritic tree. Through a clearer understanding of cerebellar microcircuitry, we may potentially identify new therapeutic strategies for the treatment of cerebellar specific motor deficits.

描述（由申请人提供）：小脑主要负责通过处理和修改皮质的降低电动机命令来协调运动运动。一般小脑电路相当同质。然而，在此微电路内的不同突触连接处存在相当大的异质性。初步研究表明，在单个平行纤维末端的谷氨酸释放调节比最初报告的可变性更大。该建议的目的是通过仔细研究单个平行纤维 - 星状细胞突触来更好地理解平行纤维的信号传导特性。 AIM 1将研究负责激活O的谷氨酸的来源。这项工作将确定动作潜在依赖性，同步释放或动作潜在独立的异步释放是引起NMDA受体电流所需的谷氨酸释放的主要方法。使用谷氨酸的2光子激光衰老，AIM 2将通过模仿异步和多源释放来确定NMDAR激活的程度。该目标还将确定NMDAR是局部邻触临时还是均匀分散在整个星状细胞树突树中。通过更清楚地了解小脑微电路，我们可能有可能确定用于治疗小脑特定运动缺陷的新治疗策略。