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.

项目摘要/摘要 阿尔茨海默氏病（AD）是痴呆症的最常见形式，也是第六个主要死亡原因 影响570万美国人的美国。广告无法治愈，自最新广告以来已有15年 纪念品药物已获得FDA的批准。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。这种行为无法通过神经元的突然损失或增益来解释 神经原纤维缠结或β-淀粉样斑块。相反，广告患者经历的清醒时刻可能 代表正常神经元网络活动的出现，该活动受广告中的病理事件的破坏 脑。在AD患者和AD的小鼠模型中，神经元网络超同步（癫痫样 观察到放电和癫痫发作）和振荡网络活性（脑节律）改变。最近的 发现表明，抑制性神经元功能障碍是导致网络的关键上游机制 高度同步，降低行为依赖性的γ振荡能力和认知功能受损 AD的J20模型。在AD患者和AD小鼠模型中发现抑制性神经元的缺陷 顶叶皮层中电压门控钠河道亚基1.1的水平降低。 NAV1.1 主要在白蛋白（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性。 PV中间神经元对于调节至关重要 然而，与认知相关的γ振荡活性，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中伽马节奏的破坏和网络超同步。 使用体内两光子成像，脑电图（EEG）记录和行为评估， 体内PV细胞活性与行为固定的J20小鼠的γ振荡之间的关系改变 将确定（目标1）。此外，长期的脑电图记录将有助于剖析PV的作用 脑状态和疾病状态依赖性网络超同步中的神经元（AIM 2）。完成 在该奖项的指导阶段的前两个目标将允许全面发展创新 技术，可以使抑制性中间神经元与其他的新研究方向 大脑中的细胞类型，以确定AD中神经元功能障碍的原因和作用。在 该奖项的独立阶段，AIM 3调查了光伏中间神经元的体内功能障碍如何 兴奋性神经元活性的失调，导致振荡活性改变和网络 J20小鼠的高度同步。遗传NAV1.1过表达将用于调节PV细胞功能获得 在所有三个目标中的进一步机械洞察力。长期目标是了解抑制性中间神经元如何 调节大脑中的振荡节奏以改变认知功能。这种机械洞察力可能有可能 通过操纵抑制性神经元和网络来改善AD患者的认知功能 功能，类似于具有清醒力矩的AD患者，无论大脑中其他病理如何。