Maintenance of proper protein homeostasis is an essential activity of mammalian cells. Alterations at the level of RNA binding proteins (RBPs) have recently been described as a central event in many pathologies and often play a central role in neurodegenerative (ND) diseases. One of the main RBPs involved in these processes is TDP-43, particularly in the ND pathologies Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD). Our general objective is to study whether changes in neuronal activation and plasticity play a role in TDP-43-mediated pathogenesis using a murine model of proteinopathies. In particular, we will use transgenic mice that conditionally overexpress a mutated cytoplasmic form (TDP-43-ΔNLS) of human TDP-43 in forebrain neurons in order to: a) establish the impact of local/global changes in neuronal activation and plasticity in the behavioral deficits mediated by alterations in TDP-43; and b) determine if the pharmacological modulation of the BDNF/TrkB pathway (which regulates neuronal activity/plasticity) using the drug LM22A-4 has therapeutic potential in our preclinical ALS/FTD model. Using approaches at biochemical, pharmacological and behavioral levels, we aim to analyze the pathophysiological roles of TDP-43. The results of this project will allow us to shed light on the pathogenic mechanisms underlying TDP-43 proteinopathies, which in turn will be vital to development new and more effective therapies targeting this group of diseases.