Coexistence of perseveration and apathy in the TDP-43Q331K 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-43Q331K knock-in mouse model of ALS-FTD. Translational Psychiatry (In Press).

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 (TDP43Q331K) 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, TDP43Q331K 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 TDP43Q331K 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.

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