PT  - JOURNAL ARTICLE
AU  - Scekic-Zahirovic, Jelena
AU  - Sanjuan-Ruiz, Inmaculada
AU  - Kan, Vanessa
AU  - Megat, Salim
AU  - De Rossi, Pierre
AU  - Dieterlé, Stéphane
AU  - Cassel, Raphaelle
AU  - Kessler, Pascal
AU  - Wiesner, Diana
AU  - Tzeplaeff, Laura
AU  - Demais, Valérie
AU  - Muller, Hans-Peter
AU  - Picchiarelli, Gina
AU  - Mishra, Nibha
AU  - Dirrig-Grosch, Sylvie
AU  - Kassubek, Jan
AU  - Rasche, Volker
AU  - Ludolph, Albert
AU  - Boutillier, Anne-Laurence
AU  - Polymenidou, Magdalini
AU  - Lagier-Tourenne, Clotilde
AU  - Liebscher, Sabine
AU  - Dupuis, Luc
TI  - Cytoplasmic accumulation of FUS triggers early behavioral alterations linked to cortical neuronal hyperactivity and defects in inhibitory synapses
AID  - 10.1101/2020.06.09.141556
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.06.09.141556
4099  - http://biorxiv.org/content/early/2020/06/11/2020.06.09.141556.short
4100  - http://biorxiv.org/content/early/2020/06/11/2020.06.09.141556.full
AB  - 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 profound increase in neuronal activity in the frontal cortex of Fus knock-in mice in vivo. Importantly, RNAseq analysis suggested involvement of defects in inhibitory neurons, that was confirmed by ultrastructural and morphological defects of inhibitory synapses and increased synaptosomal levels of mRNAs involved in inhibitory neurotransmission. Thus, cytoplasmic FUS triggers inhibitory synaptic deficits, leading to increased neuronal activity and behavioral phenotypes. FUS mislocalization may trigger deleterious phenotypes beyond motor neuron impairment in ALS, but also in other neurodegenerative diseases with FUS mislocalization.Competing Interest StatementThe authors have declared no competing interest.