Lambourne Sarah L, Humby Trevor, Isles Anthony R, Emson Piers C, Spillantini Maria G, Wilkinson Lawrence S
Laboratory of Cognitive and Behavioural Neuroscience, The Babraham Institute, Babraham Research Campus, Cambridge CB2 4AT, UK.
Hum Mol Genet. 2007 Jul 15;16(14):1708-19. doi: 10.1093/hmg/ddm119. Epub 2007 May 20.
Abnormalities in microtubule-associated tau protein are a key neuropathological feature of both Alzheimer's disease and many frontotemporal dementias (FTDs), including hereditary FTD with Parkinsonism linked to chromosome 17 (FTDP-17). In these disorders, tau becomes aberrantly phosphorylated, leading to the development of filamentous neurofibrillary tangles in the brain. Here we report, in a longitudinal ageing study, the sensorimotor and cognitive assessment of transgenic mice expressing the human tau(V337M) ('Seattle Family A') FTDP-17 mutation, which we have previously shown to demonstrate abnormalities in brain tau phosphorylation. The data indicated highly specific effects of transgene expression on the ability to withhold responding in a murine version of the 5-choice serial reaction time task, behaviour consistent with deficits in impulse control. Ageing exacerbated these effects. In young tau(V337M) mice, increased impulsivity was present under task conditions making inhibition of premature responding more difficult (longer inter-trial intervals) but not under baseline conditions. However, when older, the tau(V337M) mice showed further increases in premature responding, including under baseline conditions. These impulse control deficits were fully dissociable from sensorimotor or motivation effects on performance. The findings recapitulate core abnormalities in impulsive responding observed in both frontal variant FTD and FTDP-17 linked to the tau(V337M) mutation in humans.
微管相关的tau蛋白异常是阿尔茨海默病和许多额颞叶痴呆（FTD）的关键神经病理学特征，包括与17号染色体相关的遗传性FTD伴帕金森综合征（FTDP - 17）。在这些疾病中，tau蛋白发生异常磷酸化，导致大脑中出现丝状神经原纤维缠结。在此，我们在一项纵向衰老研究中报告了表达人类tau（V337M）（“西雅图家族A”）FTDP - 17突变的转基因小鼠的感觉运动和认知评估，我们之前已证明该突变小鼠脑内tau蛋白磷酸化存在异常。数据表明转基因表达对小鼠5选串行反应时间任务中抑制反应能力有高度特异性影响，这种行为与冲动控制缺陷一致。衰老加剧了这些影响。在年轻的tau（V337M）小鼠中，在使抑制过早反应更困难的任务条件下（更长的试验间隔）出现冲动性增加，但在基线条件下未出现。然而，老年时，tau（V337M）小鼠的过早反应进一步增加，包括在基线条件下。这些冲动控制缺陷与对行为表现的感觉运动或动机影响完全无关。这些发现概括了在人类额叶变异型FTD和与tau（V337M）突变相关的FTDP - 17中观察到的冲动反应的核心异常。
