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.

项目总结/摘要 阿尔茨海默氏病（AD）是痴呆症的最常见形式，并且是老年人的第六大死亡原因。 美国影响了570万美国人AD没有治愈方法，距离最近的AD已经15年了 美金刚已被FDA批准值得注意的是，AD患者表现出认知功能的波动 在几小时或几天内。这种行为不能用神经元的突然丧失或获得来解释， 神经纤维缠结或β-淀粉样斑块。相反，AD患者经历的清醒时刻可能 代表AD中被病理事件破坏的正常神经元网络活动的出现 个脑袋在AD患者和AD小鼠模型中，神经元网络超同步（癫痫样） 放电和癫痫发作）和改变的振荡网络活动（脑节律）。最近 研究发现，抑制性中间神经元功能障碍是导致网络的关键上游机制， 超同步性，行为依赖性伽马振荡功率降低和认知功能受损， AD的J20模型。在AD患者和AD小鼠模型中都发现了抑制性中间神经元的缺陷 其中顶叶皮质中电压门控钠通道亚基Nav1.1的水平降低。NAV1.1 主要在小清蛋白（PV）阳性抑制性中间神经元中表达， 在感觉运动和认知过程中增加的振荡活动。PV中间神经元在调节 认知相关的γ振荡活动，然而，PV中间神经元和 PV中间神经元如何促成AD中的破坏的γ节律和网络超同步尚不清楚。 使用体内双光子成像，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γ振荡改变的关系 将确定（目标1）。此外，长期EEG记录将有助于剖析PV的作用 脑状态和疾病状态依赖性网络超同步中的中间神经元（目的2）。完成 前两个目标，在指导阶段的这一奖项将允许充分发展的创新 技术，这使得一个新的研究方向对抑制性中间神经元与其他神经元的相互作用， 大脑中的细胞类型，以确定AD中中间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研究了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 在所有三个目标中进一步的机械洞察力。长期目标是了解抑制性中间神经元 调节大脑中的振荡节律以改变认知功能。这种机械的洞察力可能会 通过操纵抑制性中间神经元和网络改善AD患者认知功能 功能，类似于AD患者具有清醒的时刻，而不管大脑中的其他病理。