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）：在发育中的中枢神经系统（CNS）中形成精确的突触连接对神经功能至关重要。在视网膜和丘脑外侧膝状体核（LGN）之间的视网膜膝状体突触处，几个发育阶段有助于突触回路的形成、完善和成熟。在神经元最初映射到其目标之后，存在轴突乔木的总体形态学重排，因为视网膜神经节细胞（RGC）轴突分离成眼睛特异性层。在小鼠中，我们已经发现，长后RGC轴突分离到适当的区域的LGN（出生后第8天，p8），有两个时期的强大的突触可塑性和重塑。突触可塑性的第一阶段发生在眼睛睁开的时间（p12-14）左右，此时，对给定LGN中继神经元的一些视网膜输入增强，而其他输入被修剪。第二个，以前未被发现的可塑性阶段发生在p20之后，当视网膜膝状体突触的强度和连接变得对感觉体验敏感时。在这里，我们建议研究的形态学变化的视网膜轴突乔木，对应的两个时期的突触可塑性。为了做到这一点，我们将利用现有的转基因小鼠，并产生新的小鼠品系，其中它们的RGCs的稀疏子集共表达标记轴突乔木和突触前标记物突触素的标签，使用不同的荧光颜色。使用这些小鼠，我们将研究选择视网膜神经节细胞轴突的形态学变化和轴突乔木领土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，以及在可塑性的第二阶段对视觉剥夺的反应。我们将测试的假设，RGC轴突乔木结构是更广泛的功能所需的，并成为稳定的时间左右，眼睛睁开。我们还将研究是否强大的突触可塑性的时期代表一个固定的轴突乔木支架内的突触释放位点的重排。发现一个广泛的结构支架，其中突触接触可以形成，断裂和重新排列，这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，我们希望能够更清楚地了解突触发育的结构机制。这个项目的目标是了解神经元如何形成相互连接，称为突触。我们建议可视化突触前神经元的轴突终端的结构在发育过程中如何变化，以及轴突的形式如何与突触功能相对应。了解神经系统的正常布线是如何完成的，将有助于深入了解异常连接导致的神经系统疾病，如某些形式的精神发育迟滞，认知障碍和癫痫。