Synapse structural dynamics and memory loss in mouse models of Alzheimers disease

项目摘要/摘要 记忆储存的效果取决于兴奋性和抑制性之间的微妙平衡 突触强度和连接性(E/I平衡)。这项提议的目标是理解这种破坏是如何 在阿尔茨海默病(AD)的小鼠模型中，皮质神经元的这种平衡会导致记忆丧失。 阿尔茨海默病患者死后脑的免疫组织学研究表明，兴奋性脑组织的减少 突触密度与记忆丧失的严重程度有最强的相关性。兴奋性突触减少 密度会降低神经元的活性。相比之下，脑成像研究发现，在大脑中， 具有阿尔茨海默病遗传易感性的临床健康个体。小鼠阿尔茨海默病模型，人类家族性AD- 淀粉样前体蛋白(APP小鼠)编码基因的连锁突变也显示出兴奋性降低 突触和神经元过度活跃。在这项提案中，我们将在实验中调和这些对比 观察并确定与APP小鼠记忆丧失有关的突触缺陷。 神经元的活动维持在动态范围内的设定点附近。任何对此的干扰 射程引起代偿性突触变化以实现动态平衡。因此，我们假设 APP小鼠兴奋性突触密度降低是一种对由以下因素引发的多动的稳态适应 E/I失衡。兴奋性突触的减少会导致长期记忆丧失。 我们最近开发了一种新的方法来标记和重复成像兴奋性和抑制性 用多色双光子显微镜观察活体相同皮质神经元中的突触蛋白。这种方法 使我们能够同时可视化小鼠大脑中的兴奋性和抑制性突触动力学 活体以前所未有的分辨率。此外，我们还建立了评估加速的范例 APP小鼠的遗忘(正常的短期记忆，但长期记忆受损)。加速遗忘是 最近在具有APP突变的临床健康个体中发现。我们的初步研究表明 APP小鼠形成了视觉识别记忆(VRM)，但无法将其稳定为长期记忆。 利用APP小鼠(J20和5X-FAD系)的慢性体内突触成像和VRM任务，我们将 确定1)兴奋性突触丢失是否是对多动的动态平衡适应，以及 最初的E/I失衡是由兴奋性或抑制性突触受损触发的；2)多动是否 阻止学习过程中形成的兴奋性突触的稳定，并导致加速遗忘； 3)新突触稳定性受损和突触加速失稳的相对贡献 预先存在突触中的突触蛋白在降低兴奋性突触密度中的作用。 这项拟议的研究将提供APP小鼠体内突触的最高分辨率检查 以确定并揭示记忆丧失之前的突触损伤。最重要的是，这些研究具有 有可能为AD的治疗确定新的靶点。

PROJECT SUMMARY/ABSTRACT The efficacy of memory storage is determined by the delicate balance between excitatory and inhibitory synaptic strength and connectivity (E/I balance). The goal of this proposal is to understand how the disruption of this balance in cortical neurons leads to memory loss in mouse models of Alzheimer's disease (AD). Immunohistology of postmortem brains from the AD patients shows that the reduction in excitatory synapse density is the strongest correlate for the severity of memory loss. A reduction in excitatory synapse density would lower neuronal activity. In contrast, brain imaging studies identified neuronal hyperactivity in clinically healthy individuals with a genetic predisposition for AD. Mouse models of AD, with human familial AD- linked mutations in the gene coding for amyloid precursor protein (APP mice), also display reduced excitatory synapses and neuronal hyperactivity. In this proposal, we will experimentally reconcile these contrasting observations and determine the synaptic deficits associated with memory loss in APP mice. Neuronal activity is maintained around a set point within a dynamic range. Any perturbation to this range elicits compensatory synaptic changes to achieve homeostasis. Therefore, we hypothesize that the reduction in excitatory synapse density in APP mice is a homeostatic adaptation to hyperactivity triggered by E/I imbalance. The reduction in excitatory synapses then causes long-term memory loss. We recently developed a novel approach to label and repeatedly image excitatory and inhibitory synaptic proteins in the same cortical neurons in vivo using multicolor two-photon microscopy. This approach has allowed us to simultaneously visualize excitatory and inhibitory synapse dynamics in the mouse brain in vivo with an unprecedented resolution. In addition, we have established a paradigm for assessing accelerated forgetting (normal short-term but an impaired long-term memory) in APP mice. Accelerated forgetting was recently discovered in clinically healthy individuals with APP mutations. Our preliminary studies indicate that the APP mice form a visual recognition memory (VRM) but are unable to stabilize it as long-term memory. Using chronic in vivo synapse imaging and the VRM task in APP mice (J20 and 5X-FAD lines), we will determine 1) whether excitatory synapse loss is a homeostatic adaptation to hyperactivity and whether the initial E/I imbalance is triggered by impairments to excitatory or inhibitory synapses; 2) whether hyperactivity prevents the stabilization of excitatory synapses formed during learning and leads to accelerated forgetting; and 3) the relative contribution of impaired stabilization of new synapses and accelerated destabilization of synaptic proteins in pre-existing synapses in reducing excitatory synapse density. The proposed studies will provide the highest resolution examination of synapses in APP mice in vivo to date and reveal synaptic impairments that precede memory loss. Most importantly, these studies have the potential to identify new targets for the treatment of AD.