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

项目概要/摘要： 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。

Project Summary/Abstract: 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.