CONDITIONAL MOUSE MODELS OF TDP-43 PROTEINOPATHIES

LIONEL MÜLLER IGAZ

Buenos Aires

Conferencia; Molecular Mechanisms in Tissue Degeneration and Regeneration; 2015

"International Centre for Genetic Engeneering and Biotechnology" (ICGEB, Italy) and "Ministerio de Ciencia, Tecnología e Inovación Productiva" (MINCyT, Argentina)

TDP-43 mislocalization and aggregation are hallmark features of amyotrophic lateral sclerosis and frontotemporal dementia (FTD). We have previously shown in mice that inducible overexpression of a cytoplasmically-localized form of TDP-43 (TDP-43-ΔNLS) in forebrain neurons evokes neuropathological changes that recapitulate several features of TDP-43 proteinopathies. Detailed behavioral phenotyping could provide further validation for its usage as a model for FTD. In the present study, we performed a battery of behavioral tests to evaluate motor, cognitive and social phenotypes in this model. We found that transgene (Tg) induction by doxycycline (dox) removal at weaning led to motor abnormalities including hyperlocomotion in the open field test, impaired coordination and balance in the rotarod test and increased spasticity as shown by a clasping phenotype. Cognitive assessment demonstrated impaired recognition and spatial memory, measured by novel object recognition and Y-maze tests. Remarkably, TDP-43-ΔNLS mice displayed deficits in social behavior, mimicking a key aspect of FTD. In order to analyze if these symptoms were reversible, we suppressed Tg expression for 14 d in young mice, which showed an established behavioral phenotype but modest neurodegeneration, and found that motor and cognitive deficits were ameliorated; however, social performance remained altered. When older mice (exhibiting overt neurodegeneration) were suppressed with dox, the motoric phenotypes were not reversible. These results indicate that TDP-43-ΔNLS mice display several core behavioral features of FTD with motor neuron disease, possibly due to functional changes in the surviving neurons, and might serve as a valuable tool to unveil the underlying mechanisms of this and other TDP-43 proteinopathies.