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

项目总结/摘要 记忆储存的功效是由兴奋性和抑制性之间的微妙平衡决定的 突触强度和连接性（E/I平衡）。本提案的目标是了解 皮质神经元的这种平衡导致阿尔茨海默病（AD）小鼠模型的记忆丧失。 AD患者死后大脑的免疫组织学显示， 突触密度与记忆丧失的严重程度最密切相关。兴奋性突触减少 密度会降低神经元的活动。相比之下，脑成像研究发现， 具有AD遗传易感性的临床健康个体。AD的小鼠模型，与人类家族性AD- 编码淀粉样前体蛋白的基因中的连锁突变（APP小鼠）也显示出兴奋性降低， 突触和神经元过度活跃。在这个建议中，我们将通过实验来调和这些对比 观察并确定与APP小鼠记忆丧失相关的突触缺陷。 神经元活动维持在动态范围内的设定点附近。任何干扰 增强代偿性突触变化以达到体内平衡。因此，我们假设， APP小鼠兴奋性突触密度的减少是对由 E/I不平衡。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图像兴奋和抑制 突触蛋白在相同的皮质神经元在体内使用双光子显微镜。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， vivo以前所未有的分辨率。此外，我们还建立了一个评估加速 遗忘（正常的短期记忆，但受损的长期记忆）在APP小鼠。加速遗忘 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小鼠形成视觉识别记忆（VRM），但不能将其稳定为长期记忆。 在APP小鼠（J20和5X-FAD系）中使用慢性体内突触成像和VRM任务，我们将 确定1）兴奋性突触丧失是否是对过度活跃的稳态适应，以及 初始E/I失衡是由兴奋性或抑制性突触的损伤触发的; 2）是否过度活动 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; 和3）新突触的稳定性受损和突触的加速不稳定的相对贡献。 在降低兴奋性突触密度中，预先存在的突触中的突触蛋白。 拟议的研究将提供APP小鼠体内突触的最高分辨率检查 并揭示记忆丧失前的突触损伤。最重要的是，这些研究 有可能发现治疗AD的新靶点。

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.