The Dynamics of Synaptic Component at the Neuromuscular Junction of Living Animal

项目总结 我们的长期目标是更好地了解神经递质受体密度是如何维持的 并在体内调节成熟和发育中的突触。我们用的是神经肌肉 连接(NMJ)，运动神经元和肌肉纤维之间的兴奋性胆碱能突触，如 我们的模型系统，因为这种疾病对人类健康的重大影响 Synapse，因为它提供了最易访问的模型系统来研究 神经递质受体在体内的循环。直到最近，受体回收还被认为是一种 中枢神经系统中神经递质受体的专有特性，但我们 发现大量的乙酰胆碱受体(AChRs)被回收到 内化后的突触后膜，有助于维持 成熟突触上受体的突触后密度。我们将追求两个目标来评估 在突触发育和成熟过程中循环的潜在作用和测试 有可能参与回收过程的分子的作用。我们有 重点阐述了α-dystrobrevin和α-syntroin在调节细胞周期中的作用。 Achr的突触后膜，因为这些蛋白质的突变明显 与人类神经肌肉传递障碍有关，以及这些基因的突变 已经被证明可以显著改变成熟突触上的AChR数量， 如果受体回收异常，这是可以预料到的。了解病毒的分子基础 受体循环可以带来更有效的干预和治疗，这可能会增加 神经肌肉疾病中通过增加AChR数量或密度进行突触传递。 此外，受体回收的某些方面似乎对所有细胞都是共同的， 因此，我们预计这些结果将不仅有助于理解 神经肌肉连接，但将提供对受体循环在脑内的长期作用的见解。 较难接近的中央突触的突触发生和突触可塑性。

PROJECT SUMMARY Our long term goal is to better understand how neurotransmitter receptor density is maintained and regulated at mature and developing synapses in vivo. We are using the neuromuscular junction (NMJ), an excitatory cholinergic synapse between motor neurons and muscle fibers as our model system, because of the significant impact on human health of disorders at this synapse and because it provides the most accessible model system to study the process of neurotransmitter receptor recycling in vivo. Until recently receptor recycling was thought to be an exclusive property of neurotransmitter receptors in the central nervous system, but we discovered that significant numbers of acetylcholine receptors (AChRs) are recycled back onto the postsynaptic membrane after internalization, contributing to the maintenance of the postsynaptic density of receptors at mature synapses. We will pursue two goals to assess potential roles for recycling during synaptic development and in maturity and two goals to test the roles of molecules that are strong candidates for participation in the recycling process. We have focused on the roles of alpha-dystrobrevin and alpha-syntrophin in regulating the recycling of AChR onto the postsynaptic membrane because mutations in these proteins are clearly associated with human disorders of neuromuscular transmission, and mutations of these genes in mice have been demonstrated to dramatically alter the number of AChR at mature synapses, as might be expected if receptor recycling was aberrant. Understanding the molecular basis of receptor recycling could lead to more effective intervention and therapy that could increase synaptic transmission by increasing AChR number or density in neuromuscular diseases. Furthermore, it seems likely that some aspects of receptor recycling will be common to all cells, so we expect that these results will be useful not only in understanding the development of the neuromuscular junction, but will provide insights into the long-term role of receptor recycling in synaptogenesis and synaptic plasticity at less accessible central synapses.