Coexistence of perseveration and apathy in the TDP-43^Q331K knock-in mouse model of ALS–FTD

Kim, Eosu; White, Matthew A.; Phillips, Benjamin U.; Lopez-Cruz, Laura; Kim, Hyunjeong; Heath, Christopher J.; Lee, Jong Eun; Saksida, Lisa M.; Sreedharan, Jemeen and Bussey, Timothy J. (2020). Coexistence of perseveration and apathy in the TDP-43^Q331K knock-in mouse model of ALS–FTD. Translational Psychiatry, 10(1), article no. 377.

DOI: https://doi.org/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-43^Q331K mouse, an ALS–FTD model with a human-equivalent mutation (TDP-43^Q331K) 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-43^Q331K 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-43^Q331K 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-43^Q331K 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-43^Q331K mice exhibit a perseverative phenotype with some evidence of apathy-like behaviour, similar to BPSDs observed in human ALS–FTD patients. The TDP-43^Q331K 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.

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