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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.

项目总结/文摘