Cytoplasmic FUS triggers early behavioral alterations linked to cortical neuronal hyperactivity and inhibitory synaptic defects
Jelena Scekic‐Zahirovic, Inmaculada Sanjuan-Ruiz, Vanessa W. Y. Kan, Salim Megat, Pierre De Rossi, Stéphane Dieterle, Raphaelle Cassel, Marguerite Jamet, Pascal Kessler, Diana Wiesner, Laura Tzeplaeff, Valérie Demais, Sonu Sahadevan, Katharina Hembach, Hans‐Peter Müller, Gina Picchiarelli, Nibha Mishra, Stefano Antonucci, Sylvie Dirrig‐Grosch, Jan Kassubek, Volker Rasche, Albert C. Ludolph, Anne‐Laurence Boutillier, Francesco Roselli, Magdalini Polymenidou, Clotilde Lagier‐Tourenne, Sabine Liebscher, Luc Dupuis
Abstract
Gene mutations causing cytoplasmic mislocalization of the RNA-binding protein FUS lead to severe forms of amyotrophic lateral sclerosis (ALS). Cytoplasmic accumulation of FUS is also observed in other diseases, with unknown consequences. Here, we show that cytoplasmic mislocalization of FUS drives behavioral abnormalities in knock-in mice, including locomotor hyperactivity and alterations in social interactions, in the absence of widespread neuronal loss. Mechanistically, we identified a progressive increase in neuronal activity in the frontal cortex of Fus knock-in mice in vivo, associated with altered synaptic gene expression. Synaptic ultrastructural and morphological defects were more pronounced in inhibitory than excitatory synapses and associated with increased synaptosomal levels of FUS and its RNA targets. Thus, cytoplasmic FUS triggers synaptic deficits, which is leading to increased neuronal activity in frontal cortex and causing related behavioral phenotypes. These results indicate that FUS mislocalization may trigger deleterious phenotypes beyond motor neuron impairment in ALS, likely relevant also for other neurodegenerative diseases characterized by FUS mislocalization.