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Published on: May 28, 2017
Impairments in impulse control in mice transgenic for the human FTDP-17 tauV337M mutation are exacerbated by age
Sarah L Lambourne1, Trevor Humby, Anthony R Isles
1Laboratory of Cognitive and Behavioural Neuroscience, The Babraham Institute, Babraham Research Campus, Cambridge CB2 4AT, UK.
Abstract:
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.
Insights
Transgenic mice with a human tau mutation linked to frontotemporal dementia (FTD) show impulse control deficits. These deficits worsen with age, mirroring human FTD symptoms.
Area of Science:
- Neuroscience
- Genetics
- Neuropathology
Background:
- Abnormal tau protein phosphorylation is central to Alzheimer's disease and frontotemporal dementias (FTDs).
- Hereditary FTD with Parkinsonism linked to chromosome 17 (FTDP-17) involves tau mutations.
- The tau(V337M) mutation is associated with FTDP-17 and altered brain tau phosphorylation.
Purpose of the Study:
- To assess sensorimotor and cognitive function in transgenic mice expressing the human tau(V337M) mutation.
- To investigate the longitudinal effects of ageing on these functions.
- To determine if tau(V337M) expression causes specific behavioral deficits related to impulse control.
Main Methods:
- Longitudinal ageing study involving transgenic mice expressing human tau(V337M).
- Assessment using a murine version of the 5-choice serial reaction time task.
- Analysis of sensorimotor, cognitive, and motivational performance, distinguishing impulse control.
Main Results:
- Tau(V337M) expression specifically impaired the ability to withhold responding, indicating impulse control deficits.
- Ageing exacerbated these impulse control deficits in the transgenic mice.
- Deficits were observed under challenging conditions in young mice and baseline conditions in older mice, dissociable from other performance factors.
Conclusions:
- The tau(V337M) mutation in mice leads to specific impulse control impairments.
- These findings suggest a direct link between tau pathology and executive function deficits.
- The mouse model recapitulates key behavioral abnormalities seen in human FTDP-17 and frontal variant FTD.
