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

阿尔茨海默病小鼠模型中的突触结构动力学和记忆丧失

基本信息

批准号：
10599269
负责人：
Jaichandar Subramanian
金额：
$ 36.62万
依托单位：
UNIVERSITY OF KANSAS LAWRENCE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-15 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10599269
关键词：
Ablation Acceleration Affect Age Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease patient Amyloid beta-Protein Precursor Autopsy Brain Brain imaging Cause of Death Chronic Clinical Code Color DLG4 gene Epilepsy Equilibrium Excitatory Synapse Exhibits Functional disorder Genes Genetic Predisposition to Disease Goals Homeostasis Hour Human Human Amyloid Precursor Protein Hyperactivity Image Impairment Individual Inhibitory Synapse J20 mouse Label Learning Link Memory Memory Loss Mus Mutation Neurons Pathology Patients Pilot Projects Proteins Resolution Role Severities Stimulus Synapses Synaptic plasticity Testing Time United States Venus Vertebral column Visual Visual Cortex Visualization area striata base comparison control density deprivation epileptiform excitatory neuron experience experimental study familial Alzheimer disease forgetting gephyrin imaging approach imaging study in vivo in vivo imaging inducible gene expression long term memory memory recognition mouse model novel strategies overexpression pharmacologic postsynaptic preservation prevent recruit synaptic failure synaptogenesis translational approach two photon microscopy visual deprivation

项目摘要

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.

项目摘要/摘要存储器存储的功效取决于兴奋性和抑制性之间的微妙平衡突触强度和连通性（E/I平衡）。该提议的目的是了解干扰皮质神经元中这种平衡导致阿尔茨海默氏病小鼠模型（AD）的记忆力丧失。 AD患者的尸体大脑的免疫组织学表明兴奋性的降低突触密度对于记忆丧失的严重程度是最强的相关性。减少兴奋性突触密度将降低神经元活性。相反，脑成像研究确定了神经元的多动症临床健康的个体，具有AD遗传易感性。 AD的小鼠模型，具有人类家族性AD- 编码淀粉样前体蛋白（APP小鼠）的基因中连接的突变，也显示出降低的兴奋性突触和神经元多动。在此提案中，我们将通过实验来调和这些对比观察并确定与App小鼠中记忆丧失相关的突触缺陷。神经元活动在动态范围内的设定点附近保持。对此的任何扰动范围引发补偿性突触变化以实现稳态。因此，我们假设 APP小鼠中兴奋性突触密度的降低是对触发的多动症的稳态适应 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颖的方法来标记和反复形象兴奋性和抑制作用使用多色双光子显微镜在体内同一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小鼠大脑中的兴奋性和抑制性突触动态具有前所未有的分辨率的体内。此外，我们建立了一个用于评估加速的范式忘记应用小鼠（正常的短期但长期记忆受损）。加速遗忘是最近在具有应用程序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），但无法稳定为长期内存。使用慢性体内突触成像和App Mice中的VRM任务（J20和5X-FAD线），我们将确定1）兴奋性突触损失是否是对多动症的体内平衡适应最初的E/I不平衡是由兴奋性或抑制突触的损害引起的。 2）多动症防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）新突触稳定和加速稳定的相对贡献在降低兴奋性突触密度的预先存在突触中的突触蛋白。拟议的研究将在体内对App Mice的突触进行最高的分辨率检查迄今为止并揭示在记忆丧失之前的突触障碍。最重要的是，这些研究具有潜力确定新目标以治疗AD。