Visualizing Remodeling at the Retinogeniculate Synapse

视网膜突触重塑的可视化

• 批准号: 7293314
• 负责人: Chinfei Chen
• 金额: $ 21.13万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-30 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7293314
• 关键词: Age; Animals; Area; Axon; Chromosome Pairing; Cognition Disorders; Color; DNA Sequence Rearrangement; Development; Epilepsy; Exhibits; Eye; Goals; Grant; In Vitro; Label; Lateral Geniculate Body; Maps; Measures; Mental Retardation; Morphology; Mus; Nervous System Physiology; Nervous system structure; Neuraxis; Neuronal Plasticity; Neurons; Numbers; Phase; Physiological; Presynaptic Terminals; Relative (related person); Retina; Retinal; Retinal Ganglion Cells; Sensory; Site; Structure; Synapses; Synaptic plasticity; Synaptophysin; System; Testing; Thalamic structure; Time; Transgenic Mice; base; day; experience; eye formation; insight; nervous system disorder; novel; postnatal; presynaptic; response; retinal axon; retinogeniculate; scaffold; segregation; spatial relationship; synaptic function; visual deprivation

DESCRIPTION (provided by applicant): The formation of precise synaptic connections in the developing central nervous system (CNS) is critical for neurological function. At the retinogeniculate synapse, the connection between the retina and the lateral geniculate nucleus (LGN) of the thalamus, several developmental phases contribute to the formation, refinement and maturation of synatic circuits. After the initial mapping of a neuron to its target, there is gross morphological rearrangement of the axon arbors, as retinal ganglion cell (RGC) axons segregate into eye-specific layers. In the mouse, we have found that long after RGC axons segregate into the proper region of the LGN (postnatal day 8, p8), there are two periods of robust synaptic plasticity and remodeling. The first phase of synaptic plasticity occurs around the time of eye opening (p12-14) when some of the retinal inputs to a given LGN relay neuron strengthened while other inputs are pruned. A second, previously undetected, phase of plasticity occurs after p20, when the strength and connectivity of the retinogeniculate synapse becomes sensitive to sensory experience. Here we propose to study the morphological changes of retinal axon arbors that correspond to the two periods of synaptic plasticity. To do this, we will take advantage of available transgenic mice, and also generate new mouse lines in which a sparse subset of their RGCs co-express labels that tag axon arbors and the presynaptic marker, synaptophysin, using different fluorescent colors. Using these mice, we will examine changes in the morphology of select retinal ganglion cell axons and the relative distribution of the synaptic contacts within an axon arbor territory. These changes will be quantified as the connection remodels during normal development, and in response to visual deprivation during the second phase of plasticity. We will test the hypothesis that the RGC axon arbor structure is broader that functionally necessary and becomes stable around the time of eye opening. We will also examine whether the periods of robust synaptic plasticity represent rearrangements of synaptic release sites within a fixed axon arbor scaffold. A finding of a broad structural scaffold in which synaptic contacts can form, break and rearrange may represent a relatively novel type of neural plasticity. By relating structure to function, we hope to gain clearer understanding of the structural mechanisms that underlie synaptic development. The goal of this project is to understand the how neurons form connections, called synapses, with each other. We propose to visualize how the structure of the axon terminals of presynaptic neurons change during development and how axonal form corresponds with synaptic function. Understanding how normal wiring of the nervous system is accomplished will provide insight into neurological disorders that result from aberrant connections, such as some forms of mental retardation, cognitive disorders and epilepsy.

描述（由申请人提供）：发展中枢神经系统（CNS）中精确突触连接的形成对于神经功能至关重要。在视网膜生成的突触中，丘脑的视网膜和侧向基因核（LGN）之间的连接有助于促进，有助于造型的神经回路的形成，完善和成熟。在将神经元映射到其靶标之后，视网膜神经节细胞（RGC）轴突将轴突的形态重排有总体形态重排，将其分离为特异性层。在小鼠中，我们发现在RGC轴突隔离到LGN的适当区域（产后第8天，P8）之后很长时间，有两个鲁棒的突触可塑性和重塑的时期。突触可塑性的第一阶段发生在开眼界的时间（P12-14）左右，当时某些视网膜输入对给定的LGN继电器神经元增强，而其他输入则被修剪。 p20之后发生了第二个以前未被发现的可塑性，当时视网膜生成突触的强度和连通性对感觉体验敏感。在这里，我们建议研究与突触可塑性两个时期相对应的视网膜轴突轴测的形态变化。为此，我们将利用可用的转基因小鼠，并生成新的鼠标线条，其中使用不同的荧光颜色，其RGCS共表达标签的稀疏子集将轴突Arbors和突触前标记物（突触突触标记）标记。使用这些小鼠，我们将检查选择视网膜神经节细胞轴突的形态变化以及轴突植物区域内突触接触的相对分布。这些变化将被量化为正常发育过程中的连接重塑，并响应可塑性第二阶段的视觉剥夺。我们将检验以下假设：RGC轴突轴突结构在功能上更为必要，并且在开眼界范围内变得稳定。我们还将检查稳健的突触可塑性的周期是否代表固定轴突arbor支架内突触释放位点的重排。发现突触接触可以形成，断裂和重新排列的广泛结构支架可能代表了一种相对新颖的神经可塑性。通过将结构与功能联系起来，我们希望对突触发展构成的结构机制有更清晰的了解。该项目的目的是了解神经元如何形成称为突触的连接方式。我们建议可以看到突触前神经元的轴突末端的结构在发育过程中的变化以及轴突形式如何与突触功能相对应。了解神经系统的正常接线将提供对因异常连接（例如某些形式的智力低下，认知障碍和癫痫）等神经系统疾病的见解。