The role of cortical neuron and circuit function in tau induced neurodegeneration

描述（由申请人提供）： 编码微管相关蛋白tau的基因突变可能导致人类毁灭性的神经退行性疾病。先前在人类和小鼠中的研究表明，突触丢失是tau介导的神经变性中最早的事件之一。然而，直到最近，还不可能评估这种突触丢失对完整大脑中细胞和回路功能的影响。该提案中提出的研究将：1）确定突变tau蛋白表达如何影响小鼠大脑皮层内神经元的自发和诱发活动，2）表征突变tau蛋白表达对皮层信息处理的后果，3）评估突变tau蛋白引起的局部皮层回路功能障碍。 这些研究将使用体内双光子成像与钙指标，以确定突触缺陷如何导致tau介导的疾病小鼠模型中的细胞和系统功能障碍。我预计，这些研究将提高目前对神经退行性变的起始事件以及神经活动如何在表达tau突变形式的大脑中受损的理解。 公共卫生相关性： 我们对神经退行性疾病的理解存在巨大的差距，存在于突触发生的分子事件和患有这些毁灭性疾病的人的认知能力下降之间。神经元蛋白tau的功能障碍是许多神经退行性疾病如阿尔茨海默病、皮克病和额颞叶痴呆的标志，并且已知会破坏突触信号传导并导致认知能力下降。该提案旨在通过使用转基因小鼠疾病模型和活脑内活性的体内双光子成像的强大工具来确定突变tau对神经元活性和神经回路功能的影响，从而弥合我们理解中的差距。

DESCRIPTION (provided by applicant): Mutations in the gene encoding the microtubule associated protein tau can lead to devastating neurodegenerative diseases in humans. Previous studies in humans and mice have shown that synapse loss is one of the earliest events in tau-mediated neurodegeneration. Until recently however, it has been impossible to assess the effects of this synapse loss on the function of cells and circuits in the intact brain. The studies put forward in this proposal will: 1) determine how mutant tau expression affects the spontaneous and evoked activity of neurons within the mouse cerebral cortex, 2) characterize the consequences of mutant tau expression on cortical information processing, and 3) assess the dysfunction of local cortical circuits caused by mutant tau. These studies will use in vivo two-photon imaging with calcium indicators to determine how synaptic defects lead to cellular and system-wide dysfunction in mouse models of tau-mediated disease. I anticipate that these studies will improve the current understanding of the initiating events of neurodegeneration and how neural activity is compromised in brains expressing mutant forms of tau. PUBLIC HEALTH RELEVANCE: A tremendous gap in our understanding of neurodegenerative diseases lies between the molecular events that occur at the synapse and the cognitive decline of people suffering from these devastating diseases. The dysfunction of the neuronal protein tau is a hallmark of many neurodegenerative diseases such as Alzheimer's Disease, Pick's Disease and Frontotemporal Dementia, and is known to disrupt synaptic signaling and lead to cognitive decline. This proposal aims to bridge the gap in our understanding by determining the effects of mutant tau on neuronal activity and neural circuit function by using the powerful tools of transgenic mouse models of disease and in vivo two-photon imaging of activity within the living brain.