Impairments in impulse control in mice transgenic for the human FTDP-17 tauV337M mutation are exacerbated by age.
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.
Lambourne
Sarah L
SL
Laboratory of Cognitive and Behavioural Neuroscience, The Babraham Institute, Babraham Research Campus, Cambridge CB2 4AT, UK.
Humby
Trevor
T
Isles
Anthony R
AR
Emson
Piers C
PC
Spillantini
Maria G
MG
Wilkinson
Lawrence S
LS
D000367:Age Factors; D000375:Aging; D000818:Animals; D001921:Brain / Q000378:metabolism; D002886:Chromosomes, Human, Pair 17; D003704:Dementia / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D007174:Disruptive, Impulse Control, and Conduct Disorders / Q000235:genetics*; D020869:Gene Expression Profiling; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D013116:Spinal Cord / Q000378:metabolism; D013997:Time Factors; D016875:tau Proteins / Q000235:genetics* / Q000378:metabolism
D016875:tau Proteins