Plasticity of the retinogeniculate synapse

描述（由申请人提供）：发育过程中突触回路形成和完善的机制是一个深入研究的课题。在中枢神经系统的许多突触中，最初的连接是多余的。然而，这些联系在发展过程中被细化，因为不必要的联系被消除，适当的联系被加强。我们的特点是在一个强大的模型突触发育，视网膜神经节细胞和丘脑的外侧膝状体核的丘脑中继神经元之间的连接突触功能的变化。利用电生理学技术和小鼠脑切片制备，我们发现了一个以前未被认识的阶段的经验依赖性突触重塑的视网膜神经突触。在大量突触消除和突触加强发生后的某个时间，我们发现黑暗饲养导致的剥夺导致电路重组，因为视网膜和丘脑之间的连接变得更弱，更丰富。这种后期的重塑是由睁眼后一周的视觉体验激活的。我们的研究结果表明，在发育的后期，丘脑中的突触有一个时期是出乎意料的可塑性，RGC和丘脑中继神经元之间的配对可以重新连接。在这里，我们建议定义控制这一可塑性时期的机制。首先，我们将确定我们在LGN的感觉依赖期观察到的连接变化的结构基础。其次，我们将确定和表征丘脑视觉依赖性可塑性的分子机制。最后，我们将研究皮层对视网膜膝状体发育的影响。这些研究的结果将为我们理解发育后期奠定基础，在发育后期，丘脑中的兴奋性突触回路是由外部环境塑造的。丘脑中的连接可以以经验依赖的方式重塑，这一发现对我们理解成熟和发育中的大脑具有重要意义。由于感觉信息通过丘脑传递到皮层，丘脑回路的中断会导致异常的信息处理和皮层功能。因此，阐明驱动丘脑可塑性的机制将是高度相关的，我们了解神经发育障碍，包括精神发育迟滞，自闭症，癫痫和认知疾病。 公共卫生相关性：我们之前已经发现，在发育后期，丘脑（大脑皮层下区域，负责处理传入信息并将信息传递到皮层）的突触回路可以通过经验进行重塑。在这项研究中，我们建议确定触发，维持和结束这一时期的强大突触可塑性的重要机制。了解这些基本过程可能有助于指导未来因异常突触连接导致的神经系统疾病（如某些形式的癫痫，认知障碍和精神发育迟滞）的治疗设计。

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.