Human Molecular Genetics Advance Access published online on May 20, 2007
Human Molecular Genetics, doi:10.1093/hmg/ddm119
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Impairments in impulse control in mice transgenic for the human FTDP-17 tauV337M mutation are exacerbated by age
1 Laboratory of Cognitive and Behavioural Neuroscience, The Babraham Institute, Babraham Research Campus, Cambridge, CB2 4AT, UK 2 Behavioral Genetics Group, Cardiff University, UK, School of Psychology and Department of Psychological Medicine, Cardiff, CF14 4XN, UK 3 Laboratory of Molecular Neuroscience, The Babraham Institute, Babraham Research Campus, Cambridge, CB2 4AT, UK 4 Centre for Brain Repair and Department of Clinical Neurosciences, University of Cambridge, Cambridge, CB2 2PY, UK
* Correspondence and requests for materials should be addressed to LS Wilkinson: Tel. ++44 (0) 2920 870357/(0) 2920 747942, Fax. ++44 (0) 2920 874858, Email. wilkinsonl{at}cardiff.ac.uk
Received February 23, 2007; Revised April 27, 2007; Accepted April 27, 2007
Abnormalities in microtubule associated tau protein are a key neuropathological feature of both Alzheimer's disease (AD) and many frontotemporal dementias (FTDs), including hereditary Frontotemporal Dementia 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 tauV337M ("Seattle Family A") FTDP-17 mutation, which we have previously shown 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 (5-CSRTT), behaviour consistent with deficits in impulse control. Ageing exacerbated these effects. In young tauV337M 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 tauV337M 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 (fvFTD) and FTDP-17 linked to the tauV337M mutation in humans.
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