EVALUATION OF COGNITIVE, MOTOR AND SOCIAL PHENOTYPES IN TWO RODENT MODELS OF NEURODEGENERATIVE DISEASE

ALFIERI JA; SILVA PR; IGAZ LM

Montevideo

Congreso; 12th International Congress of Neuroethology; 2016

International Society for Neuroethology

Frontotemporal Dementia (FTD) and amyotrophic lateral sclerosis (ALS) are two human neurodegenerative diseases associated to mislocalization and aggregation of the nuclear protein TDP-43. We have previously shown in mice that inducible overexpression of human nuclear wild-type TDP-43 protein (hTDP-43-WT) or a cytoplasmically localized form (hTDP-43-NLS) in forebrain neurons evokes neuropathological changes that recapitulate several features of TDP-43 proteinopathies. We conducted a variety of behavioral tests to evaluate the effect of TDP-43 on motor, cognitive and social function. Our results indicate that hTDP-43-NLS mice develop motor abnormalities, including a dramatically altered rotarod performance, a spontaneous hyperlocomotor phenotype and pathological abnormal limb clasping as early as 2-4 weeks post transgene induction. hTDP-43-NLS mice also showed altered social investigation behavior, a hallmark feature of FTD patients. Furthermore we found significant deficits in cognitive function in novel object recognition, inhibitory avoidance and Y-maze tests at 1 month post-induction. We also determined that young hTDP-43-WT transgenic mice, in opposition to hTDP-43-NLS mice, present a normal motor phenotype compared to control littermates, as assessed by rotarod performance, spontaneous locomotor activity and a milder degree of spasticity. We are currently performing a broader behavioral characterization which suggests an impairment in cognitive and social domains in the absence of overt motor abnormalities, providingfurther validation for the use of these mice to model different aspects of FTD/ALS. These results will contribute to address in vivo the pathogenic mechanisms underlying TDP-43 proteinopathies.