INVESTIGATING THE EARLY FRONTOTEMPORAL DEMENTIA PHENOTYPES IN A MOUSE MODEL OF TDP-43 PROTEINOPATHY

Frontotemporal dementia (FTD) is a fatal neurodegenerative disease affecting the frontal and temporal lobes, with behavioural variant FTD being characterized by social impairment, executive dysfunction and personality changes. FTD and amyotrophic lateral sclerosis (ALS) lie on a shared disease spectrum, with 30-50% of patients exhibiting both cognitive and motor symptoms, and the majority of FTD-ALS cases are characterized by TDP-43 pathology. This study uses a tetracycline-repressible TDP-43 mouse model replicating FTD-ALS pathology targeting all neurons, showing motor impairment, brain atrophy, and reversible disease progression. This work investigates the cognitive changes during early disease stages of FTD-ALS.
Here, FTD phenotypes are investigated using behavioural paradigms assessing changes in activity, exploration, anxiety, memory and sociability. Mice were tested at three timepoints: preinduction, one week and two weeks postinduction. Conventional behavioural analysis showed hyperactivity, decreased sociability, and changes to anxiety-like behaviour. Unsupervised machine learning was employed to identify subtle changes to behavioural phenotype, revealing decrease in behavioural motifs including standing-still and sniffing, as well as increased locomotion, turning and rearing across behavioural paradigms. These changes indicate hyperactivity and altered exploration, as well as stereotypic behaviour. Moreover, anatomical investigations suggest changes in interneuron populations within the medial prefrontal cortex at the same timepoints.Current fiber photometry experiments are investigating functional changes in interneuron activity associated with behavioural changes. In conclusion, we were able to identify milder, clinically relevant phenotypes at early stages, recapitulating FTD symptoms and with potential to investigate system-level effects of TDP-43 expression.

Funding: St Leonard’s college, Royal Society, RS Macdonald