Effect size of memory deficits in mice with adult-onset P301L tau expression

Abstract

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.

Longitudinal evaluation of Tau‐P301L transgenic mice reveals no cognitive impairments at 17 months of age

“…Considering the LR deficit observed here and the fact that spatial deficits have been reported in these mice at younger ages (Murakami et al., ), future studies of this model should prioritize early detection of hippocampus‐dependent deficits. For example, there is some evidence that mice expressing the P301L transgene are particularly impaired in trace fear conditioning relative to other hippocampal‐dependent tasks such as the MWM (Hunsberger et al., ); thus, researchers using TgTau P301 mice might consider employing trace fear conditioning tasks to detect the earliest memory deficits.…”

Riluzole rescues glutamate alterations, cognitive deficits, and tau pathology associated with P301L tau expression

“…At 2.5 months of age, while still on DOX to suppress tau expression, mice underwent behavioral testing in the water radial arm maze (WRAM) to establish that cognitive deficits were dependent upon tau expression as previously described (Hunsberger et al 2014b) ( Fig. 1).…”

Altered Synapse Stability in the Early Stages of Tauopathy

“…However, it was recently shown that neuronal firing patterns are altered as early as 5 months of age, leading to the suggestion that perturbations in coordinated synaptic activity may occur in early-stage pathology (Menkes-Caspi et al., 2015). Most importantly, deficits in cognitive function seem to emerge in advance of major histopathology (Hunsberger et al., 2014), as suggested for dementia (Sperling et al., 2011). Therefore, pursuing the hypothesis that synaptic dysfunction is an early harbinger of dementia, we have determined when and how changes in synapse number are first manifested in rTg4510 mice.…”