SHORT-TERM SUPPRESSION OF TDP-43-NLS OVEREXPRESSION REVERSES BEHAVIORAL DEFICITS IN A FRONTOTEMPORAL DEMENTIA TRANSGENIC MOUSE MODEL.

ALFIERI JA; PINO DELGADO N; DOMBROVSKY NS; LUCHELLI L; IGAZ LM

Huerta Grande, Córdoba

Congreso; XXVIII Congreso Anual de la Sociedad Argentina de Investigación en Neurociencias (SAN).; 2013

Sociedad Argentina de Investigación en Neurociencias (SAN).

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-NLS) 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-NLS 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-NLS 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-NLS overexpression in young mice reversibly affects normal neuronal function, which might account for the behavioral deficits observed in these mice.