Translational modulation by ISRIB alleviates synaptic and behavioral phenotypes in Fragile X syndrome

Abstract

Fragile X syndrome (FXS) is caused by the functional loss of Fragile X messenger ribonucleoprotein (FMRP), a translational regulator that binds the transcripts of many proteins involved in synaptic function and plasticity. Dysregulated protein synthesis is a central effect of FMRP loss and to date direct translational modulation has not been leveraged in the treatment of FXS. Thus, we examined the effect of the small molecule translational modulator, Integrated Stress Response Inhibitor (ISRIB), in treating synaptic and behavioral symptoms of FXS. Using a combination of population-level single synapse analysis, in vivo two-photon microscopy, and behavioral analysis, we revealed a mechanism for the appearance of dense and immature dendritic spines, which are observed in human FXS patients and Fmr1 knockout (KO) mice. Our data suggest that FMRP loss at the synapse dysregulates synaptic protein abundance and that spines are disproportionately stabilized through increased PSD-95 expression but prevented from maturing through reduced synaptic accumulation of glutamate receptors. ISRIB rescues these molecular and synaptic deficits in FXS and improves social recognition in Fmr1 KO mice. These findings highlight the therapeutic potential of targeting core translational mechanisms and the differential impact of FMRP on synaptic and cellular function in FXS and neurodevelopmental disorders more broadly.