Evaluation of behavioral phenotypes before and after transgene suppression in a conditional TDP-43 mouse model of Frontotemporal dementia /Amyotrophic lateral sclerosis.

NIEVA, GABRIELA V.; SILVA, PABLO R.; IGAZ, LIONEL M.

Mar del Plata

Congreso; XXXII Congreso Sociedad Argentina de Investigación en Neurociencia; 2017

Mislocalization and aggregation of TDP-43 are two common features of frontotemporal dementia (FTD) as well as amyotrophic lateral sclerosis (ALS). We developed transgenic mice conditionally overexpressing human wild-type TDP-43 protein (hTDP-43- WT) in forebrain neurons, a model that recapitulate key features of FTD/ALS. After post-weaning transgene (TG) induction during 1 month, these mice display an early behavioral phenotype, including impaired cognitive and social function with no substantial motor abnormalities. In this study we evaluated the behavior before and after 2 weeks of TG suppression. hTDP-43-WT mice evaluated in the Y-maze test displayed normal spatial and working memory both before and after the suppression protocol. This indicates that TG suppression prevents the installment of early cognitive deficits. TG suppression also prevented the development of the mild spasticity observed in mice expressing the TG for 1 month. Both locomotion and exploratory behavior (open field test) and motor coordination (rotarod test) were indistinguishable from controls before and after TG suppression. Since the results of these tests were consistent with the ones seen after 1 month of TG expression, the suppression protocol had no unspecific effects on motor behavior. No social deficits were found before TG suppresion. These results contribute to our understanding of FTD/ALS and provide valuable information for susceptibility windows in therapeutic strategies.