Cytoplasmic FUS triggers early behavioral alterations linked to cortical neuronal hyperactivity and inhibitory synaptic defects

Scekic-Zahirovic, Jelena; Sanjuan-Ruiz, Inmaculada; Kan, Vanessa; Megat, Salim; De Rossi, Pierre; Dieterle, Stephane; Cassel, Raphaelle; Jamet, Marguerite; Kessler, Pascal; Wiesner, Diana; Tzeplaeff, Laura; Demais, Valerie; Sahadevan, Sonu; Hembach, Katharina M.; Muller, Hans-Peter; Picchiarelli, Gina; Mishra, Nibha; Antonucci, Stefano; Dirrig-Grosch, Sylvie; Kassubek, Jan; Rasche, Volker; Ludolph, Albert; Boutillier, Anne-Laurence; Roselli, Francesco; Polymenidou, Magdalini; Lagier-Tourenne, Clotilde; Liebscher, Sabine und Dupuis, Luc (2021): Cytoplasmic FUS triggers early behavioral alterations linked to cortical neuronal hyperactivity and inhibitory synaptic defects. In: Nature Communications, Bd. 12, Nr. 1, 3028

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. Mutations in the RNA binding protein FUS are associated with ALS. Here the authors show that in FUS knock-in mice there is a progressive increase in neuronal activity in the frontal cortex which is associated with altered synaptic gene expression.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin ; Medizin > Munich Cluster for Systems Neurology (SyNergy)
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 2041-1723
• Sprache: Englisch
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198