Plasticity of the retinogeniculate synapse

描述（由申请人提供）：突触回路在发育过程中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，初始连接是过多和冗余的。然而，这些联系在发展过程中得到完善，不必要的联系被消除，适当的联系得到加强。我们已经在突触发育的强大模型中描述了突触功能的变化，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。利用电生理技术和小鼠脑切片制备，我们发现了视网膜原状突触中一个以前未被认识到的经验依赖性突触重构阶段。在大量突触消除和突触加强发生后，我们发现，由于视网膜和丘脑之间的连接变得更弱和更丰富，黑暗饲养的剥夺导致了电路的重组。这种后期的重塑是由睁眼后一周内的视觉体验激活的。我们的研究结果表明，在发育后期有一段时间，丘脑中的突触出乎意料地具有可塑性，RGC和丘脑中继神经元之间的配对可以重新连接。在这里，我们建议定义控制这一可塑性时期的机制。首先，我们将确定我们在LGN感觉依赖期间观察到的连通性变化的结构基础。其次，我们将识别和表征丘脑视觉依赖可塑性的分子机制。最后，我们将研究皮层对视网膜回鞘发育的影响。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层的，丘脑回路的中断会导致信息处理和皮层功能的异常。因此，阐明驱动丘脑可塑性的机制将对我们理解神经发育障碍（包括智力迟钝、自闭症、癫痫和认知疾病）具有重要意义。

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.