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

项目摘要/摘要 阿尔茨海默病(AD)是最常见的痴呆症形式，是世界上第六大致死原因。 这影响了570万美国人。阿尔茨海默病没有治愈的方法，距离最近的一次AD已经过去了15年 药物美金刚获得了FDA的批准。值得注意的是，AD患者的认知功能出现波动 在几小时或几天的过程中。这种行为不能用神经元的突然丧失或增加来解释， 神经纤维缠结或β-淀粉样斑块。相反，AD患者可能会经历清醒的时刻 代表AD中正常神经元网络活动的出现，该活动被病理事件破坏 大脑。在AD患者和AD小鼠模型中，神经元网络超同步性(癫痫样 观察到放电和癫痫)和改变的振荡网络活动(大脑节律)。近期 研究表明，抑制性神经元间功能障碍是导致网络的关键上游机制 超同步性、行为依赖型伽马振荡功率降低和认知功能受损 AD的J20型号。在AD患者和AD小鼠模型中均发现抑制性中间神经元缺陷 在顶叶皮质，电压门控钠通道亚单位Nav1.1的水平降低。Nav1.1 主要表达在小白蛋白(PV)阳性的抑制性中间神经元，它产生伽马 感觉运动和认知过程中增加的振荡活动。PV中间神经元在调制过程中起关键作用 然而，与认知相关的伽马振荡活动，在体内的PV中间神经元和 目前尚不清楚PV中间神经元如何参与阿尔茨海默病的伽马节律紊乱和网络超同步。 利用活体双光子成像、脑电(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的关系 将被确定(目标1)。此外，长期的脑电记录将有助于剖析PV的作用 脑状态和疾病状态依赖网络中的中间神经元超同步(目标2)。已完成的 在这个奖项的指导阶段的前两个目标将允许一个创新的 技术，这为抑制中间神经元与其他神经元的相互作用提供了一个新的研究方向 以确定AD患者中间神经元功能障碍的原因和影响。在.期间 该奖项的独立阶段，Aim 3调查了PV中间神经元在体内的功能障碍如何导致 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的过度表达将用于调节光伏细胞的功能以获得 在所有三个目标中进一步机械性的洞察。长期目标是了解抑制性中间神经元是如何 调节大脑的振荡节奏以改变认知功能。这种机械论的洞察力可能会 通过操纵抑制性中间神经元和网络改善AD患者的认知功能 功能，类似于阿尔茨海默病患者的清醒时刻，与大脑中的其他病理无关。

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.