title: Mutant Tau knock-in mice display frontotemporal dementia relevant behaviour and histopathology.
abstract: 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 (~60kDa) in forebrain samples, we identified age-dependent progressive Tau phosphorylation which coincided with the emergence of FTD relevant behavioural traits. In line with the non-cognitive symptomatology of FTD, PLB2Tau mice demonstrated early emerging (~6months) 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 home cage corner-learning task. Spatial learning was only mildly affected and task-specific, with impairments at 12months 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 non-rapid 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 a striking behavioural and physiological face validity relevant for FTD, driven by the low level expression of mutant FTD hTau.
authors.affiliation: School of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK.
authors.forename: David J
authors.initials: DJ
authors.lastname: Koss
authors.affiliation: School of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK.
authors.forename: Lianne
authors.initials: L
authors.lastname: Robinson
authors.affiliation: School of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK.
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Drever
authors.affiliation: School of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK.
authors.forename: Kaja
authors.initials: K
authors.lastname: Plucińska
authors.affiliation: School of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK.
authors.forename: Sandra
authors.initials: S
authors.lastname: Stoppelkamp
authors.affiliation: School of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Veselcic
authors.affiliation: School of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK. Electronic address: g.riedel@abdn.ac.uk.
authors.forename: Gernot
authors.initials: G
authors.lastname: Riedel
authors.affiliation: School of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK. Electronic address: b.platt@abdn.ac.uk.
authors.forename: Bettina
authors.initials: B
authors.lastname: Platt
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology*; D004195:Disease Models, Animal; D057180:Frontotemporal Dementia / Q000473:pathology* / Q000503:physiopathology; D055879:Gene Knock-In Techniques / Q000379:methods; D017774:Long-Term Potentiation / Q000235:genetics*; D008568:Memory / Q000502:physiology*; D008822:Mice, Transgenic; D016874:Neurofibrillary Tangles / Q000378:metabolism; D009473:Neuronal Plasticity / Q000235:genetics; D009435:Synaptic Transmission / Q000235:genetics; D024801:Tauopathies / Q000473:pathology; D016875:tau Proteins / Q000235:genetics* / Q000378:metabolism*
chemical_list: D016875:tau Proteins
keywords: Anhedonia; Apathy; Cognition; EEG; Frontotemporal dementia; Phosphorylation; Semantic memory; Spatial memory; Tau; Tauopathies