Disinhibition-like behavior in a P301S mutant tau transgenic mouse model of frontotemporal dementia

Abstract

Frontotemporal dementia (FTD) presents clinically with behavioral changes including disinhibition. Mutations in the tau-encoding MAPT gene identified in familial cases of FTD have been used to generate transgenic mouse models of the human condition. Here, we report behavioral changes in a recently developed P301S mutant tau transgenic mouse, including disinhibition-like behavior in the elevated plus maze and hyperactivity in the open field arena. Furthermore, histological analysis revealed the amygdala as a primary and early site of pathological tau deposition in these mice. Taken together, neuropathological and behavioral changes in P301S tau transgenic mice resemble features of human FTD. Disciplines Medicine and Health Sciences | Social and Behavioral Sciences Publication DetailsPrzybyla, M., Stevens, C. H., van der Hoven, J., Harasta, A., Bi, M., Ittner, A., van Hummel, A., Hodges, J. R., Piguet, O., Karl, T., Kassiou, M., Housley, G. Approximately one third of FTD cases are familial with the most frequent mutations found in the tau-encoding MAPT 13 gene with tau pathology, and in GRN and C9ORF72 associated with TDP-43 deposition [10]. Interestingly, behavioral 14 disinhibition is more frequent amongst MAPT, than GRN and C9ORF72 mutation carriers with familial FTD [21]. 15 16 Tau is an unstructured multi-domain protein that binds to microtubules to regulate their dynamics and intracellular 17 transport processes [2]. Tau is predominantly found in the axon of neurons, although small amounts localize to the post -18 synapse to regulate excitatory signaling [15]. Tau harbors over 80 potential phosphorylation sites, and in disease, it 19 becomes aberrantly phosphorylated at many sites, which coined the term 'hyperphosphorylated tau' [11]. 20Hyperphosphorylation of tau compromises its binding to microtubules, resulting in accumulation of tau in the soma and 21 dendrites of neurons [13]. Hyperphosphorylated tau is prone to oligomerize and form insoluble fibrillar aggregates that 22 present as neurofibrillary tangles (NFTs), a common feature of FTD with tau pathology [5]. 23 24 The identification of MAPT mutations in familial FTD has been instrumental in the generation of a significant number 25 of transgenic mouse lines that develop functional deficits and NFT pathology (reviewed by [12]). We have recently 26 reported TAU58/2 mice with neuronal expression of P301S mutant tau [24]. TAU58/2 mice present with motor deficits , 27 and tau and neurofillament pathology reminiscent of human FTD with tau pathology. In the present study, we show that 28 TAU58/2 mice develop early-onset disinhibition-like behavior and increased motor activity together with early NFT 29 pathology in the amygdala, reminiscent of bvFTD. Open Field 5Activity, anxiety and exploration pattern were tested in 3, 6 and 10 month-old male TAU58/2 mice (n=6-17) and non-6 transgenic littermates (n=6-13) in an open field arena. Mice were individually placed at the periphery of a box (40cm x 7 40cm) in an enclosed cupboard and their movement ...

Early Cognitive/Social Deficits and Late Motor Phenotype in Conditional Wild-Type TDP-43 Transgenic Mice

“…They also show signs of a mild decrease in anxiety in the elevated plus maze test, which some authors interpret as disinhibition and might indicate alterations in amygdala or prefrontal cortex function (Roberson, 2012; Koss et al, 2016). These phenotypes are consistent with those observed in other FTD mouse models (Takeuchi et al, 2011; Przybyla et al, 2016; Vernay et al, 2016a), although in some FTD models an increase in anxiety was also reported (Koss et al, 2016; Liu et al, 2016). Further analysis are required to clearly define if some form of disinhibition is present in tTA/WT12 mice.…”

“…These data argues against an unspecific effect on non-motor behaviors due to increased anxiety or impaired visual function. Additionally, they suggest that TDP-43-WT mice may show disinhibition, as reported in other mouse models for FTD (Yin et al, 2010; Ke et al, 2015; Przybyla et al, 2016). …”

Behavioural impairments in mice of a novel FUS transgenic line recapitulate features of frontotemporal lobar degeneration

“…In the elevated O‐maze transgenic mice also spent more time exploring the open arm. Short latency time to exit from the dark compartment is a parameter that reflecting impulsivity and the increased exploratory interest in the light compartments is an indicator of decreased anxiety, which could be interpreted as excessive risk‐taking behaviour and/or disinhibition or even emotional dysfunction, which are often observed in FTLD patients …”

“…[24][25][26] ments is an indicator of decreased anxiety, which could be interpreted as excessive risk-taking behaviour and/or disinhibition or even emotional dysfunction, which are often observed in FTLD patients. 28 The development of a memory deficit is not uncommon in FTLD patients and therefore we studied formation of memory in L-FUS mice using the extinction fear conditioning test. In mice, freezing in response to an adverse stimulus, like an electric shock used in this test, reflects their formation of memory to the context.…”

Early microgliosis precedes neuronal loss and behavioural impairment in mice with a frontotemporal dementia-causing CHMP2B mutation

“…These findings are not universal, however. Increased time in the open arms of an elevated plus-maze is observed in certain Grn- deficient mutants (42), tau-encoding MAPT transgenics (46,47) as well as the CamKIIa-driven CHMP2B model (38). Yet a different Grn- deficient mutant (43) and the recently described PLB tau model – a mutant that expresses a single copy of human FTD-associated mutant tau – both show heightened anxiety (48).…”