Coexistence of perseveration and apathy in the TDP-43Q331K knock-in mouse model of ALS\u2013FTD

Eosu Kim,Laura Lopez-Cruz,Christopher J Heath,Jong Eun Lee,Lisa M Saksida,Hyunjeong Kim,Timothy J Bussey,Matthew A White,Jemeen Sreedharan,Benjamin U Phillips

doi:10.1038/s41398-020-01078-9

Abstract

Perseveration and apathy are two of the most common behavioural and psychological symptoms of dementia (BPSDs) in amyotrophic lateral sclerosis–frontotemporal dementia (ALS–FTD). Availability of a validated and behaviourally characterised animal model is crucial for translational research into BPSD in the FTD context. We behaviourally evaluated the male TDP-43Q331K mouse, an ALS–FTD model with a human-equivalent mutation (TDP-43Q331K) knocked into the endogenous Tardbp gene. We utilised a panel of behavioural tasks delivered using the rodent touchscreen apparatus, including progressive ratio (PR), extinction and visual discrimination/reversal learning (VDR) assays to examine motivation, response inhibition and cognitive flexibility, respectively. Relative to WT littermates, TDP-43Q331K mice exhibited increased responding under a PR schedule. While elevated PR responding is typically an indication of increased motivation for reward, a trial-by-trial response rate analysis revealed that TDP-43Q331K mice exhibited decreased maximal response rate and slower response decay rate, suggestive of reduced motivation and a perseverative behavioural phenotype, respectively. In the extinction assay, TDP-43Q331K mice displayed increased omissions during the early phase of each session, consistent with a deficit in activational motivation. Finally, the VDR task revealed cognitive inflexibility, manifesting as stimulus-bound perseveration. Together, our data indicate that male TDP-43Q331K mice exhibit a perseverative phenotype with some evidence of apathy-like behaviour, similar to BPSDs observed in human ALS–FTD patients. The TDP-43Q331K knock-in mouse therefore has features that recommend it as a useful platform to facilitate translational research into behavioural symptoms in the context of ALS–FTD.

Highlights

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) exist on a clinicopathological spectrum, referred to as amyotrophic lateral sclerosis–frontotemporal dementia (ALS–FTD) complex or FTD with motor neuron disease[1,2]
In PR8, no main effect of genotype was detected on breakpoint or total touches (Fig. 1E, F), but reward collection latency was significantly increased in the TDP-43Q331K group (Fig. 1G)
43Q331K mouse, a new model of ALS–FTD, exhibits a perseverative phenotype that may mask apathy assessed by progressive ratio (PR) schedules

Summary

Introduction

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) exist on a clinicopathological spectrum, referred to as ALS–FTD complex or FTD with motor neuron disease[1,2]. ALS–FTD mouse model harbouring a human-equivalent point mutation (TDP-43Q331K) in the endogenous mouse Tardbp gene[12,14,15]. The TDP43Q331K mouse demonstrates altered splicing of the Mapt gene, which encodes the protein tau, which is closely associated with FTD pathogenesis[16]. This knock-in model may have greater translational value than other existing transgenic models as the observed phenotypes cannot be overexpression artefacts and are more likely to reflect pathogenic changes that occur in human ALS–FTD14

Methods

Results

Conclusion