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

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.

Synaptic FUS accumulation triggers early misregulation of synaptic RNAs in a mouse model of ALS

“…4j, and Supplementary data 3), while GluN1 clusters appeared unaffected. Increase in VGAT suggested an elevated number of presynaptic GABAergic vesicles, which was confirmed by EM analyses in older mice 45 . Correlatively, increase of GABA A α3 cluster size suggested an increase in the trafficking of GABA A R at the postsynaptic site.…”

“…Altogether, our results point to a critical role for FUS at the synapse and indicate that increased synaptic FUS localization in ALS-FUS mice triggers early alterations of synaptic RNA content and misregulation of the GABAergic network. These early synaptic changes correlate with the behavioral dysfunctions that these mice develop 45 .…”

“…FUS binding on multiple exonic sites was enriched within aberrantly increased mRNAs pointing to a molecular code for FUS-mediated synaptic RNA regulation. Our data indicate that early synaptic alterations in the GABAergic network precede motor impairments in these ALS-FUS mice 44 , and may trigger early behavioral dysfunctions, such as hyperactivity and social disinhibition 45 . Importantly, we show that increased synaptic localization of FUS, in the absence of aggregation, suffices to cause synaptic impairment.…”

“…This suggests a potential role for FUS in synaptogenesis and network wiring and synaptic maintenance, with a selective exacerbation of inhibitory synaptic defects with age. These early synaptic changes mechanistically explain the behavioral dysfunctions that these mice develop 45 . In particular, Fus ΔNLS/+ mice displayed increased locomotor activity at 4 months of age, while motor symptoms start at 10 months of age 44 .…”

“…In particular, Fus ΔNLS/+ mice displayed increased locomotor activity at 4 months of age, while motor symptoms start at 10 months of age 44 . Moreover, they exhibit impairments in long-term memory consolidation and social inhibition starting from 10 months of age 45 .…”