Investigating Cognitive Impairment in TDP-43 Mouse Models of FTD-ALS Using Automated Touchscreens

Keon Coleman, The University of Western Ontario

Abstract

TAR-DNA-binding protein 43 (TDP-43) misfolding and aggregation is a major pathological hallmark of frontotemporal dementia-amyotrophic lateral sclerosis (FTD/ALS). FTD/ALS is characterized by motor and cognitive impairment, with cognitive impairment frequently reported before the onset of classical motor symptoms. Yet, treatment for cognitive decline in FTD/ALS is lacking, and robust cognitive phenotypes related to TDP-43 proteinopathy have not been established for most mouse models of FTD/ALS. Herein, we used automated touchscreen technology to assess executive function (affected in FTD/ALS) in male TDP-43^Q331Klow and ^-G348C FTD/ALS transgenic mice. The touchscreen pairwise visual discrimination task revealed impairments in 4-5-month-old TDP-43^Q331Klow and ^-G348C mutants during acquisition and reversal phases. These cognitive impairments manifested prior to motor symptoms. This pattern of results is highly similar to observations in human FTD/ALS. Together, these findings identify the combination of TDP-43 mouse models and touchscreen tests as potentially useful tools for understanding and developing cognitive therapies in FTD/ALS.