DECREASED PROTEIN LEVELS OF PLASTICITY-RELATED GENES ZIF268, ARC AND c-FOS IN TDP-43-ΔNLS TRANSGENIC MICE

ALFIERI JA; DE LANDETA AB; KATCHE C; IGAZ LM

Buenos Aires

Congreso; XXX Congreso Anual de la Sociedad Argentina de Investigación en Neurociencias (SAN); 2015

Sociedad Argentina de Investigación en Neurociencias (SAN)

Recent studies demonstrated that TDP-43 is a major disease protein in frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). In these TDP-43 proteinopathies, TDP-43 is redistributed from its normal nuclear localization and form cytoplasmic insoluble aggregates. We generated a new animal model based on the conditional overexpression in the mouse forebrain of a cytoplasmically-localized form of human TDP-43 (hTDP-43-DNLS), and recently showed that these mice recapitulate key aspects of FTLD/ALS, including behavioral and cognitive deficits. However, the physiological role of TDP-43 in behavioral responses is not well understood. In this context, we aimed to assess changes in plasticity-related pathways, specifically analyzing well-known gene products involved in neural plasticity (Arc, c-fos, Zif268). Immunofluorescence staining of several brain areas (involved in processing of the behavioral tasks impaired in these mice) revealed a profound decrease of all three genes in transgenic versus control mice. Since these genes are upregulated upon behavioral challenges and are necessary for cognitive processing, we also evaluated the response to exposure to an open field test. TDP-43 transgenic mice display a reduced or absent induction of all three genes in cortical and hipocampal regions. These results suggest a novel TDP-43 driven mechanism underlying the behavioral abnormalities displayed by TDP-43 mice and potentially in human TDP-43 proteinopathies.