Short-term Suppression of TDP-43-ΔNLS Overexpression Reverses Behavioral Deficits in a Frontotemporal Dementia Transgenic Mouse Model

ALFIERI JULIO; PINO DELGADO NATALIA; DOMBROVSKY NILDA; LUCHELLI LUCIANA; MULLER IGAZ LIONEL

Cordoba

Congreso; Congreso Argentino de Neurociencias; 2013

Sociedad Argentina de Neurociencias

TDP-43 is a predominantly nuclear DNA/RNA binding protein that has been reported to regulate transcription, pre-mRNA splicing and stability. It has recently been identified as a pathological hallmark of the neurodegenerative disorders amyotrophic lateral sclerosis (ALS) and fronto-temporal lobar degeneration (FTLD). Using a transgenic (Tg) mouse model that conditionally overexpresses a cytoplasmically-localized form of human TDP-43 (TDP-43-ΔNLS) in the forebrain, we conducted a variety of behavioral tests to evaluate the effect of TDP-43 on motor, cognitive and social function. Our results indicate that TDP-43-ΔNLS transgenic mice develop motor abnormalities, including a dramatically altered rotarod performance, a spontaneous hyperlocomotor phenotype and pathological abnormal limb clasping as early as 2 weeks post-Tg induction. TDP-43-ΔNLS mice also showed altered social investigation behavior, a hallmark feature of FTLD patients. Furthermore we found significant deficits in cognitive function in novel object recognition, inhibitory avoidance and Y-maze tests at 1 month post-induction. Remarkably, we found that suppression of Tg expression for 2 weeks completely reversed the motor abnormalities. However, we found no differences in cortical neuronal loss compared to mice with continued Tg expression, suggesting that TDP-43-ΔNLS overexpression in young mice reversibly affects normal neuronal function, which might account for the behavioral deficits observed in these mice.