The role of glial cells in synapse remodeling in aging living mice

描述（由申请人提供）：在上个世纪，医学创新大大延长了人类的寿命。然而，仍然没有办法减缓大脑衰老或治疗与衰老有关的神经病变。在我们的神经系统中，神经胶质细胞的数量超过神经元，神经胶质-神经元的相互作用对突触的形成和稳定至关重要。众所周知，在正常衰老和神经退行性脑（如阿尔茨海默病和帕金森病）中，突触都发生结构改变和功能下降。然而，到目前为止，对这种突触变化的动力或胶质细胞的作用（如果有的话）知之甚少。研究突触/神经胶质细胞在衰老过程中变化的最好方法是在一个活的动物身上随时间跟踪同一突触/神经胶质细胞。目前，由于大脑中神经元/胶质细胞类型的可变性和其突触的小尺寸，这种在体内的研究还不容易在大脑中实现。脊椎动物神经肌肉连接（NMJ）是神经系统中最简单的突触。从历史上看，它对我们对突触组织和可塑性的理解做出了巨大贡献。提出的研究计划将利用小鼠NMJ作为模型系统来检查突触和相关胶质细胞（也称为终末雪旺细胞，或TSCs）在衰老过程中的结构可塑性。本研究将体内成像技术与分子检查和EM重建相结合，阐明胶质细胞在衰老过程中突触重塑中的作用。该提案有三个具体目标。目的1研究衰老过程中雪旺细胞的进行性髓鞘形成，并试图回答这种胶质变化是否会导致轴突进入部位的突触破坏，并影响整个NMJ的突触重塑。目的2研究衰老相关突触丢失的分子机制，并测试层粘连蛋白- tsc相互作用的改变是否导致肌纤维和神经末梢之间的tsc侵袭，以及这是否导致衰老过程中突触的移除。最后，Aim 3旨在确定反应性TSCs是否延长NMJs重塑过程，并引导轴突发芽和突触连接重组。这些研究的结果将为神经胶质细胞在衰老相关突触丢失中的作用提供重要的机制见解，并确定神经胶质细胞作为改善衰老相关突触病理的治疗靶点。该项目将有助于确定神经肌肉连接处在衰老过程中发生的突触变化中神经胶质细胞的作用。这些拟议的研究利用新颖的方法，使研究者能够跟踪活小鼠的胶质细胞和突触的结构变化，这将提供关于这一动态过程如何影响正常衰老的关键信息。更重要的是，这些数据可能用于创造针对神经胶质的治疗方法，以治疗以突触丧失为特征的神经退行性疾病，如帕金森病和阿尔茨海默病，或减缓正常衰老的更令人衰弱的症状。

DESCRIPTION (provided by applicant): Medical innovations have significantly prolonged the human lifespan during the last century. However, there is still no way to slow brain aging or treat aging-related neuropathologies. Glia outnumber neurons in our nervous system and glia-neuron interactions are essential for synapse formation and stability. It is known that structural alteration and functional decline occur at synapses in both normal aging and neurodegenerative brains (e.g., Alzheimer s and Parkinson s diseases). However, so far there is little known about the dynamism of this synaptic change or the role, if any, glia play. The best way to study synapse/glia changes during aging is to follow the same synapse/glia over time in a living animal. At present, such in vivo studies cannot be easily achieved in the brain, because of the variability of neuron/glia types in the brain and the small size of its synapses. The vertebrate neuromuscular junction (NMJ) is the simplest synapse in the nervous system. Historically, it has contributed greatly to our understanding of synaptic organization and plasticity. The proposed research plan will exploit the mouse NMJ as a model system to examine the structural plasticity of the synapse and associated glia (also called terminal Schwann cells, or TSCs) during aging. The proposed studies combine the in vivo imaging technique with molecular examination and EM reconstruction to elucidate the role of glia in synapse remodeling during aging. The proposal has three specific aims. Aim 1 examines progressive myelination of Schwann cells in aging and attempts to answer whether such glial changes induce synapse disruption at the axon entry site and affect synapse remodeling in the whole NMJ. Aim 2 examines the molecular mechanism underlying aging-related synapse loss, and tests whether changes in laminin-TSC interactions lead to invasion of TSCs between muscle fibers and nerve terminals, and whether this leads to removal of synapses during aging. Finally, Aim 3 is designed to determine if reactive TSCs extend processes from remodeling NMJs and guide axon sprouting and reorganization of synaptic connections. Results from the proposed studies will provide important mechanistic insights into the role of glia in aging-related synapse loss, and identify glia as a therapeutic target to ameliorate synaptic pathologies associated with aging. PUBLIC HEALTH RELEVANCE This project will help to determine the role of glial cells in synaptic changes that occur during aging at the neuromuscular junction. These proposed studies utilize novel methods that allow the investigator to follow structural changes of glia and synapses in living mice, which will provide critical information about how this dynamic process affects normal aging. More importantly, the data may be used to create therapies that target glia for the treatment of neurodegenerative diseases that are characterized by synapse loss, such as Parkinson's Disease and Alzheimer's Disease, or to slow the more debilitating symptoms of normal aging.