Functional Alterations of Parvalbumin Interneurons Contributing to Abnormal Network Activity in Alzheimer's Disease Mouse Models

小清蛋白中间神经元的功能改变导致阿尔茨海默病小鼠模型网络活动异常

• 批准号: 10750200
• 负责人: Keran Ma
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-15 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10750200
• 关键词: APP-PS1; Affect; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease therapeutic; American; Award; Bacterial Artificial Chromosomes; Behavior; Behavior assessment; Behavioral; Brain; Calcium; Cause of Death; Cell physiology; Cells; Chronic; Cognition; Cognitive; Collaborations; Color; Data; Dementia; Development; Disease; Electroencephalography; Environment; Event; Exhibits; FDA approved; Frequencies; Functional Magnetic Resonance Imaging; Functional disorder; Genetic; Goals; Head; Hour; Image; Impaired cognition; Impairment; Interneuron function; Interneurons; J20 mouse; Laboratories; Link; Literature; Locomotion; Malignant neoplasm of prostate; Measures; Memantine; Mentors; Motor Activity; Mus; Neurofibrillary Tangles; Neurons; Parietal Lobe; Parvalbumins; Pathologic; Pathology; Pattern; Pharmaceutical Preparations; Phase; Play; Predisposing Factor; Property; Publishing; Research; Resolution; Rest; Role; SCN1A protein; Scalp structure; Seizures; Senile Plaques; Sleep; Sodium Channel; Techniques; Telemetry; Therapeutic; Transgenes; Transplantation; cell type; cognitive function; cognitive task; epileptiform; excitatory neuron; experience; falls; functional outcomes; improved; in vivo; in vivo calcium imaging; in vivo two-photon imaging; innovation; insight; malignant breast neoplasm; mouse model; network dysfunction; non rapid eye movement; novel; overexpression; targeted treatment; voltage

PROJECT SUMMARY/ABSTRACT Alzheimer's disease (AD) is the most common form of dementia and the sixth leading cause of death in the U.S. that affects 5.7 million Americans. There is no cure for AD and it has been 15 years since the latest AD drug, Memantine, was approved by the FDA. Remarkably, AD patients show fluctuations of cognitive function in the course of hours or days. This behavior cannot be explained by the sudden loss or gain of neurons, neurofibrillary tangles or beta-amyloid plaques. Instead, lucid moments experienced by AD patients likely represent emergence of normal neuronal network activity that is disrupted by pathological events in the AD brain. In both AD patients and mouse models of AD, neuronal network hypersynchrony (epileptiform discharges and seizures) and altered oscillatory network activity (brain rhythms) are observed. Recent discoveries show that inhibitory interneuron dysfunction is a key upstream mechanism leading to network hypersynchrony, decreased behavior-dependent gamma oscillatory power and impaired cognitive function in the J20 model of AD. Deficits in inhibitory interneurons are found in both AD patients and mouse models of AD where levels of the voltage-gated sodium channel subunit Nav1.1 are decreased in the parietal cortex. Nav1.1 is predominantly expressed in the parvalbumin (PV)-positive inhibitory interneurons, which generate gamma oscillatory activity that increases during sensorimotor and cognitive. PV interneurons are critical in modulating cognition-associated gamma oscillatory activity, however, the in vivo functional deficits of PV interneurons and how PV interneurons contribute to disrupted gamma rhythms and network hypersynchrony in AD is unknown. Using in vivo two-photon imaging, electroencephalogram (EEG) recordings and behavioral assessments, the relationship between in vivo PV cell activity and altered gamma oscillations in behaving head-fixed J20 mice will be determined (Aim 1). Furthermore, Long-term EEG recordings will help to dissect the role of PV interneurons in brain-state- and disease-state-dependent network hypersynchrony (Aim 2). Completion of the first two aims during the mentored phase of this award will allow the full development of an innovative technique, which enables a new research direction towards the interaction of inhibitory interneurons with other cell types in the brain to determine the cause and effect of interneuron dysfunction in AD. During the independent phase of this award, Aim 3 investigates how in vivo dysfunction of PV interneurons causes dysregulation of excitatory neuron activity contributing to altered oscillatory activity and network hypersynchrony in J20 mice. Genetic Nav1.1 overexpression will be used to modulate PV cell function to gain further mechanistic insight in all three aims. The long-term goal is to understand how inhibitory interneurons modulate oscillatory rhythms in the brain to alter cognitive function. This mechanistic insight could potentially lead to improvement of cognitive function in AD patients by manipulating inhibitory interneurons and network function, similar to AD patients having lucid moments, irrespective of other pathologies in the brain.

项目概要/摘要 阿尔茨海默病 (AD) 是最常见的痴呆症，也是人类第六大死因 影响 570 万美国人的美国。 AD 无法治愈，距离最新的 AD 已经过去 15 年了 药物美金刚（Memantine）已获得 FDA 批准。值得注意的是，AD 患者表现出认知功能的波动 在几个小时或几天的过程中。这种行为不能用神经元的突然丢失或增加来解释， 神经原纤维缠结或β-淀粉样斑块。相反，AD 患者经历的清醒时刻可能是 代表 AD 中正常神经网络活动被病理事件破坏的出现 脑。在 AD 患者和 AD 小鼠模型中，神经元网络超同步（癫痫样 观察到放电和癫痫发作）和振荡网络活动（脑节律）的改变。最近的 研究发现表明抑制性中间神经元功能障碍是导致网络的关键上游机制 超同步、行为依赖性伽马振荡能力下降和认知功能受损 AD的J20型号。 AD 患者和 AD 小鼠模型均发现抑制性中间神经元缺陷 其中顶叶皮质中电压门控钠通道亚基 Nav1.1 的水平降低。导航1.1 主要表达于小清蛋白 (PV) 阳性抑制性中间神经元，产生 γ 在感觉运动和认知过程中增加的振荡活动。 PV 中间神经元对于调节至关重要 然而，认知相关的 γ 振荡活动，PV 中间神经元的体内功能缺陷和 PV 中间神经元如何导致 AD 中伽马节律紊乱和网络超同步性尚不清楚。 利用体内双光子成像、脑电图（EEG）记录和行为评估， 头部固定 J20 小鼠体内 PV 细胞活性与伽马振荡改变之间的关系 将被确定（目标 1）。此外，长期脑电图记录将有助于剖析 PV 的作用 大脑状态和疾病状态依赖性网络超同步中的中间神经元（目标 2）。完成 该奖项指导阶段的前两个目标将允许创新型项目的全面发展 技术，为抑制性中间神经元与其他神经元相互作用开辟了新的研究方向 大脑中的细胞类型可以确定 AD 中神经元功能障碍的原因和影响。期间 该奖项的独立阶段，目标 3 研究 PV 中间神经元的体内功能障碍如何导致 兴奋性神经元活动失调导致振荡活动和网络改变 J20 小鼠的超同步性。基因 Nav1.1 过表达将用于调节 PV 细胞功能以获得 对所有三个目标的进一步机械洞察。长期目标是了解抑制性中间神经元如何 调节大脑的振荡节律以改变认知功能。这种机械洞察力可能会 通过操纵抑制性中间神经元和网络改善 AD 患者的认知功能 功能，类似于具有清醒时刻的 AD 患者，无论大脑中是否有其他病变。