Spatial learning impairments in PLB1Triple knock-in Alzheimer mice are task-specific and age-dependent

Ryan, Duncan; Koss, David J.; Porcu, Emanuele; Woodcock, Hilary; Robinson, Lianne; Platt, Bettina; Riedel, Gernot

doi:10.1007/s00018-013-1314-4

Cited by 25 publications

(30 citation statements)

References 72 publications

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“…11.Aiii, genotype: F (1,1104) =28, p<0.001). Evoked fEPSP slopes were also plotted against fibre volley amplitudes, indexing the degree of pre-synaptic depolarisation required to evoke postsynaptic depolarisation (Koss et al, 2013). Here, I/O curves demonstrated reduced presynaptic efficiency in eliciting postsynaptic depolarisation at all ages in PLB2 Tau preparations compared to WT counterparts (Fig.…”

Section: D) Hippocampal Electrophysiologymentioning

confidence: 95%

“…Interestingly, we have previously reported deficits in WM acquisition at 12 months and corner learning at 4 months in the related PLB1 Triple mouse which expresses the same hTau transgene alongside mutant hAPP and PS1 Ryan et al, 2013), suggesting that the IntelliCage may be more sensitive than the WM to detect spatial learning impairments. Alternatively as PLB1 Triple mice serve as a model of AD, where spatial learning impairments are early and defining symptoms of the disease, the divergent cognitive phenotypes of PLB2 Tau and PLB1 Triple mice may highlight differential behavioural traits induced by a combination of AD and FTD-Tau familial mutations when compared to FTDTau mutants alone.…”

Section: Distinct Cognitive Deficits Of Plb2 Tau Micementioning

confidence: 96%

“…Spatial learning was investigated in PLB WT (6-month: n=19, 12-month old: n=14), and PLB2 Tau (6-month: n=19, 12-month: n=16) mice with the well-established open field water maze (WM) paradigm (see Ryan et al, 2013;Plucińska et al, 2014). Using a white Perspex water filled pool (150 cm diameter, 50 cm in height, water temp 21±1 o C), animals were allocated a fixed platform position (rising platform, Ugo Basile, Varese, Italy) and released from one of four sites along the edge of the pool, (N,E,S,W) in pseudorandom fashion.…”

Section: Spatial Learning (Open Field Water Maze)mentioning

confidence: 99%

“…The spatial learning abilities were further determined using the IntelliCage system (New Behavior, TSE-Systems Bad Homburg, Germany) as previously described (Ryan et al, 2013;Robinson and Riedel, 2014). Female mice, 6 (PLB WT : n=10 and PLB2 Tau : n=10) and 12-month old (PLB WT : n=15 and PLB2 Tau : n=13) were implanted with a unique radio transmitting microchip (Planet ID, New Behaviour) which enabled tracking and identification of individuals as they entered the experimental corners.…”

Section: Spatial Corner Learning (Intellicage)mentioning

confidence: 99%

“…Slice preparation and electrophysiological recordings were made as previously reported Koss et al, 2013). In brief, terminally anaesthetised PLB WT and PLB2 Tau mice (6, 12 and 24-month old) were decapitated, brains removed and hippocampi dissected in ice cold sucrose-based artificial cerebrospinal fluid (aCSF, mM: 249.2 sucrose, 1.5 KCl, 1.3 MgSO 4, 0.96 CaCl 2 , 1.5 KH 2 PO 4 , 2.89MgCl 2 ·6H 2 O, 25 NaHCO 3 and 10 glucose, pH 7.4, gassed with 95% O 2 / 5% CO 2 ).…”

Section: Hippocampal Slice Electrophysiologymentioning

confidence: 99%

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Mutant Tau knock-in mice display frontotemporal dementia relevant behaviour and histopathology

Koss

Robinson

Drever

et al. 2016

Neurobiology of Disease

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Models of Tau pathology related to frontotemporal dementia (FTD) are essential to determine underlying neurodegenerative pathologies and resulting Tauopathy relevant behavioural changes. However, existing models are often limited in their translational value due to Tau overexpression, and the frequent occurrence of motor deficits which prevent comprehensive behavioural assessments. In order to address these limitations, a forebrain-specific (CaMKIIα promoter), human mutated Tau (hTauP301L+R406W) knock-in mouse was generated out of the previously characterised PLB1Triple mouse, and named PLB2Tau. After confirmation of an additional hTau species (~60 kDa) in forebrain samples, we identified age-dependent progressive Tau phosphorylation which coincided with the emergence of FTD relevant behavioural traits. In line with the noncognitive symptomatology of FTD, PLB2Tau mice demonstrated early emerging (~ 6 months) phenotypes of heightened anxiety in the elevated plus maze, depressive/apathetic behaviour in a sucrose preference test and generally reduced exploratory activity in the absence of motor impairments. Investigations of cognitive performance indicated prominent dysfunctions in semantic memory, as assessed by social transmission of food preference, and in behavioural flexibility during spatial reversal learning in a homecage corner-learning task. Spatial learning was only mildly affected and task-specific, with impairments at 12-month of age in the corner learning but not in the water maze task. Electroencephalographic (EEG) investigations indicated a vigilance-stage specific loss of alpha power during wakefulness at both parietal and prefrontal recording sites, and site-specific EEG changes during nonrapid eye movement sleep (prefrontal) and rapid eye movement sleep (parietal). Further investigation of hippocampal electrophysiology conducted in slice preparations indicated a modest reduction in efficacy of synaptic transmission in the absence of altered synaptic plasticity. Together, our data demonstrate that the transgenic PLB2Tau mouse model presents with striking behavioural and physiological face validity relevant for FTD, driven by the low level expression of mutant FTD hTau. AbstractModels of Tau pathology related to frontotemporal dementia (FTD) are essential to determine underlying neurodegenerative pathologies and resulting Tauopathy relevant behavioural changes. However, existing models are often limited in their translational value due to Tau overexpression, and the frequent occurrence of motor deficits which prevent comprehensive behavioural assessments. In order to address these limitations, a forebrain-specific (CaMKIIα promoter), human mutated Tau (hTau P301L+R406W ) knock-in mouse was generated out of the previously characterised PLB1 Triple mouse, and named PLB2 Tau . After confirmation of an additional hTau species (~60 kDa) in forebrain samples, we identified age-dependent progressive Tau phosphorylation which was coincided with the emergence of FTD relevant behavioural traits. In...

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Section: D) Hippocampal Electrophysiologymentioning

confidence: 95%

Section: Distinct Cognitive Deficits Of Plb2 Tau Micementioning

confidence: 96%

Section: Spatial Learning (Open Field Water Maze)mentioning

confidence: 99%

Section: Spatial Corner Learning (Intellicage)mentioning

confidence: 99%

Section: Hippocampal Slice Electrophysiologymentioning

confidence: 99%

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Mutant Tau knock-in mice display frontotemporal dementia relevant behaviour and histopathology

Koss

Robinson

Drever

et al. 2016

Neurobiology of Disease

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Assessing Cognition in Mice

et al. 2015

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Genetically modified mouse models have proven useful to study learning and memory processes and the neurocircuitry and molecular mechanisms involved, as well as to develop therapies for diseases involving cognitive impairment. A variety of tests have been developed to measure cognition in mice, and here we present those established and regularly used in the German Mouse Clinic. The test paradigms have been carefully chosen according to reliability of results and disease relevance of the cognitive functions assessed. Further criteria were time efficiency and ease of application. All tests assess slightly different but also overlapping or interacting aspects of learning and memory so that they can be used to complement each other in a comprehensive assessment of cognitive function. The five protocols described are for spontaneous alternation in the Y-maze, social discrimination, object recognition, automated assessment of learning and memory using the IntelliCage, and olfactory discrimination learning.

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Different pathways of molecular pathophysiology underlie cognitive and motor tauopathy phenotypes in transgenic models for Alzheimer’s disease and frontotemporal lobar degeneration

Melis

Zabke

Stamer

et al. 2014

Cell. Mol. Life Sci.

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A poorly understood feature of the tauopathies is their very different clinical presentations. The frontotemporal lobar degeneration (FTLD) spectrum is dominated by motor and emotional/psychiatric abnormalities, whereas cognitive and memory deficits are prominent in the early stages of Alzheimer’s disease (AD). We report two novel mouse models overexpressing different human tau protein constructs. One is a full-length tau carrying a double mutation [P301S/G335D; line 66 (L66)] and the second is a truncated 3-repeat tau fragment which constitutes the bulk of the PHF core in AD corresponding to residues 296–390 fused with a signal sequence targeting it to the endoplasmic reticulum membrane (line 1; L1). L66 has abundant tau pathology widely distributed throughout the brain, with particularly high counts of affected neurons in hippocampus and entorhinal cortex. The pathology is neuroanatomically static and declines with age. Behaviourally, the model is devoid of a higher cognitive phenotype but presents with sensorimotor impairments and motor learning phenotypes. L1 displays a much weaker histopathological phenotype, but shows evidence of neuroanatomical spread and amplification with age that resembles the Braak staging of AD. Behaviourally, the model has minimal motor deficits but shows severe cognitive impairments affecting particularly the rodent equivalent of episodic memory which progresses with advancing age. In both models, tau aggregation can be dissociated from abnormal phosphorylation. The two models make possible the demonstration of two distinct but nevertheless convergent pathways of tau molecular pathogenesis. L1 appears to be useful for modelling the cognitive impairment of AD, whereas L66 appears to be more useful for modelling the motor features of the FTLD spectrum. Differences in clinical presentation of AD-like and FTLD syndromes are therefore likely to be inherent to the respective underlying tauopathy, and are not dependent on presence or absence of concomitant APP pathology.

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Spatial learning impairments in PLB1Triple knock-in Alzheimer mice are task-specific and age-dependent

Cited by 25 publications

References 72 publications

Mutant Tau knock-in mice display frontotemporal dementia relevant behaviour and histopathology

Mutant Tau knock-in mice display frontotemporal dementia relevant behaviour and histopathology

Assessing Cognition in Mice

Different pathways of molecular pathophysiology underlie cognitive and motor tauopathy phenotypes in transgenic models for Alzheimer’s disease and frontotemporal lobar degeneration

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