SUPPRESSION OF CONDITIONAL TDP-43 TRANSGENE EXPRESSION DIFFERENTIALLY AFFECTS EARLY COGNITIVE AND SOCIAL PHENOTYPES IN TDP-43 MICE

IGAZ LM; SILVA PR; NIEVA GV

Sydney

Conferencia; 11th International Conference on Frontotemporal Dementias; 2018

International Society for Frontotemporal Dementias

Dysregulationof the protein TDP-43 is a hallmark feature of frontotemporal dementia (FTD) andamyotrophic lateral sclerosis (ALS). We developed transgenic mice conditionallyoverexpressing human wild-type TDP-43 protein (hTDP-43-WT) in forebrainneurons, a model that recapitulates key features of FTD. 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 motorabnormalities. In this study we evaluated the behavior before (0.5mo group) andafter 2 weeks of TG suppression (1mo(sup) group), taking advantage of thefeatures of this model, which uses a system that allows for temporal andregional control of TG expression. Our main findings are: 1) Cognitiveabnormalities, represented by spatial working memory evaluated with the Y-mazetest, are not detectable after 0.5 months of hTDP-43 expression. Suppression ofTG expression with Dox at this time point prevents the development of thesedeficits observed at 1 month post-induction, as revealed by the performance ofthe 1mo(sup) group. 2) Sociability deficits, assessed through the socialinteraction test, appear very rapidly after Dox removal (0.5 mo) and TGsuppression was not sufficient to reverse this phenotype. 3) Animals evaluatedat an early time point (0.5 months) post-induction do not display a motorphenotype, in agreement with the results obtained after 1 month of TGexpression. Moreover, all motor tests (open field, accelerated rotarod, limbclasping, hanging wire grip) show identical responses in the control andbigenic animals in the suppressed group, indicating that this protocol andtreatment do not cause nonspecific effects in motor behavior, which couldpotentially mask the phenotypes in other domains. Our results show thatTDP-43-WT mice have a phenotype that qualifies them as a useful model of FTD andprovide valuable information for susceptibility windows in therapeutic strategies.