Hunsberger Holly C, Rudy Carolyn C, Weitzner Daniel S, Zhang Chong, Tosto David E, Knowlan Kevin, Xu Ying, Reed Miranda N
Department of Psychology, Behavioral Neuroscience, West Virginia University, Morgantown, WV 26506, USA.
Department of Pharmacology and Toxicology, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY 14214, USA.
Behav Brain Res. 2014 Oct 1;272:181-95. doi: 10.1016/j.bbr.2014.06.057. Epub 2014 Jul 6.
Transgenic mice expressing mutations in tau have yielded essential discoveries for Alzheimer's disease. One of the most commonly used tau mouse models is the tet-off Tg(tauP301L)4510 model that expresses P301L human tau driven by the calcium-calmodulin kinase IIα (CaMKIIα) promoter system. Tau expression in this model is regulatable, allowing for suppression of mutant tau expression until adulthood and prevention of possible developmental alterations resulting from P301L tau expression during development. Here, we compared the effect and sample sizes needed for three learning and memory tasks in mice with adult-onset P301L tau expression. Our findings indicate that the Incremental Repeated Acquisition (IRA) and trace fear conditioning tasks, neither of which have previously been published with these mice, were highly sensitive to P301L tau expression, whereas the Morris water maze, the most commonly used task with this model, was the least sensitive. Memory deficits were observed at a time when tau pathology was subtle and prior to readily detectable neuronal loss. Thus, we provide essential information (effect and sample sizes needed) for establishing experimental designs at a time point when memory deficits are likely to go undetected if inadequate sample sizes are used. Our work also suggests the tet-off Tg4510 model provides a way to avoid mutant tau expression during the perinatal and early postnatal stages, thereby preventing possible developmental alterations unrelated to Alzheimer's disease.
表达tau基因突变的转基因小鼠为阿尔茨海默病带来了重要发现。最常用的tau小鼠模型之一是四环素调控的Tg(tauP301L)4510模型，该模型由钙调蛋白激酶IIα（CaMKIIα）启动子系统驱动表达P301L人tau蛋白。该模型中tau蛋白的表达是可调节的，可抑制突变型tau蛋白的表达直至成年，并防止发育过程中因P301L tau蛋白表达而可能导致的发育改变。在此，我们比较了成年期开始表达P301L tau蛋白的小鼠在三种学习和记忆任务中的效果及所需样本量。我们的研究结果表明，增量重复获取（IRA）和痕迹恐惧条件反射任务（此前均未在这些小鼠中发表过）对P301L tau蛋白表达高度敏感，而该模型最常用的任务——莫里斯水迷宫则最不敏感。在tau病理变化尚不明显且在神经元损失易于检测之前就观察到了记忆缺陷。因此，我们提供了重要信息（所需效果和样本量），以便在使用样本量不足可能无法检测到记忆缺陷的时间点建立实验设计。我们的工作还表明，四环素调控的Tg4510模型提供了一种避免围产期和出生后早期阶段突变型tau蛋白表达的方法，从而防止与阿尔茨海默病无关的可能发育改变。
