Cytoplasmic accumulation of FUS triggers early behavioral alterations linked to cortical neuronal hyperactivity and defects in inhibitory synapses

Author:

Scekic-Zahirovic Jelena,Sanjuan-Ruiz Inmaculada,Kan Vanessa,Megat Salim,De Rossi Pierre,Dieterlé Stéphane,Cassel Raphaelle,Kessler Pascal,Wiesner Diana,Tzeplaeff Laura,Demais Valérie,Muller Hans-Peter,Picchiarelli Gina,Mishra Nibha,Dirrig-Grosch Sylvie,Kassubek Jan,Rasche Volker,Ludolph Albert,Boutillier Anne-Laurence,Polymenidou Magdalini,Lagier-Tourenne Clotilde,Liebscher Sabine,Dupuis Luc

Abstract

AbstractGene 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.

Publisher

Cold Spring Harbor Laboratory

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