Plasticity of the retinogeniculate synapse

描述(由申请人提供)：在发育过程中突触回路的形成和完善的潜在机制是一个深入研究的主题。在中枢神经系统的许多突触中，最初的连接是过度和多余的。然而，随着不必要的联系被消除，适当的联系得到加强，这些联系在发展过程中得到完善。我们已经在一个强大的突触发育模型中表征了突触功能的变化，突触发育是视网膜神经节细胞和丘脑外侧膝状核的丘脑中继神经元之间的连接。利用电生理学技术和小鼠脑片制备，我们已经发现了视网膜原基突触的经验依赖性突触重构的一个先前未知的阶段。在大量突触消除和突触加强之后，我们发现黑暗饲养的剥夺会导致回路的重组，因为视网膜和丘脑之间的联系变得更弱和更丰富。这种晚期的重塑是在睁开眼睛后的一周内由视觉体验激活的。我们的发现表明，在发育后期，丘脑中的突触出人意料地具有可塑性，RGC和丘脑中继神经元之间的配对可以重新连接。在这里，我们建议定义支配这一可塑性时期的机制。首先，我们将确定我们在LGN感觉依赖期观察到的连接性变化的结构基础。其次，我们将识别和描述丘脑视觉依赖可塑性的分子机制。最后，我们将检查皮质对视网膜原细胞发育的影响。这些研究的结果将为我们理解丘脑的兴奋性突触回路受外部环境影响的发育后期奠定基础。丘脑中的连接可以以经验依赖的方式重塑，这一发现对于我们理解成熟和发育中的大脑具有重要意义。因为感觉信息是通过丘脑传递到皮质的，丘脑回路的中断可能导致信息处理和皮质功能的异常。因此，阐明丘脑可塑性的机制对于我们理解包括智力低下、自闭症、癫痫和认知疾病在内的神经发育障碍具有重要意义。 与公共健康相关：我们之前已经发现，在发育后期，丘脑的突触电路可以通过经验重塑。丘脑是大脑中皮质下的一个区域，负责处理传入的信息并将这些信息传递到大脑皮层。在这项授权中，我们建议确定在触发、维持和结束这一强健突触可塑性时期的重要机制。了解这些基本过程可能有助于指导未来治疗因突触连接异常而导致的神经疾病的设计，如某些形式的癫痫、认知障碍和智力低下。

DESCRIPTION (provided by applicant): The mechanisms underlying the formation and refinement of synaptic circuits during development are a subject of intense investigation. At many synapses in the central nervous system, initial connections are excessive and redundant. However, these connections are refined in the course of development, as unnecessary connections are eliminated and proper ones are strengthened. We have characterized changes in synaptic function in a powerful model for synapse development, the connection between retinal ganglion cells and thalamic relay neurons of the lateral geniculate nucleus in the thalamus. Using electrophysiological techniques and a mouse brain slice preparation, we have uncovered a previously unrecognized phase of experience- dependent synapse remodeling at the retinogeniculate synapse. At a time after the bulk of synapse elimination and synaptic strengthening has occurred, we find that deprivation by dark rearing results reorganization of the circuit, as connections between retina and thalamus become weaker and more abundant. This late period of remodeling is activated by visual experience during the week after eye-opening. Our findings suggest that there is a period in late development when synapses in the thalamus are unexpectedly malleable, and that pairings between RGC and thalamic relay neurons can be rewired. Here we propose to define the mechanisms that govern this period of plasticity. First, we will determine the structural basis for the changes in connectivity that we observe during the sensory-dependent period in the LGN. Second, we will identify and characterize molecular mechanisms that underlie vision-dependent plasticity in the thalamus. Finally, we will examine the influence of the cortex on retinogeniculate development. The results from these studies will lay the groundwork for our understanding of a late developmental period during which excitatory synaptic circuits in the thalamus are shaped by the external environment. The revelation that connections in the thalamus can remodel in an experience-dependent manner has important implications for our understanding of the mature and developing brain. Because sensory information is relayed to the cortex via the thalamus, disruption in thalamic circuitry can result in aberrant information processing and cortical function. Thus elucidation of the mechanisms driving thalamic plasticity will be highly relevant for our understanding of neurodevelopmental disorders including mental retardation, autism, epilepsy and cognitive diseases. PUBLIC HEALTH RELEVANCE: We have previously discovered a period during late development when synaptic circuits in the thalamus, a subcortical region in the brain that processes incoming information and relays this information to the cortex, can be remodeled by experience. In this grant we propose to identify the mechanisms that are important in triggering, maintaining and ending this period of robust synaptic plasticity. Understanding these basic processes may help guide the design of future therapies for neurological disorders due to abnormal synaptic connections such as some forms of epilepsy, cognitive disorders and mental retardation.