Translational modulator ISRIB alleviates synaptic and behavioral phenotypes in Fragile X syndrome
Rochelle L. Coulson,
Valentina Frattini,
Caitlin E. Moyer,
Jennifer Hodges,
Peter Walter,
Philippe Mourrain,
Yi Zuo,
Gordon X. Wang
Affiliations
Rochelle L. Coulson
Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA
Valentina Frattini
Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA
Caitlin E. Moyer
National Institute on Drug Abuse, National Institutes of Health, Bethesda, MD 20892, USA
Jennifer Hodges
Department of Molecular, Cell and Developmental Biology, University of California Santa Cruz, Santa Cruz, CA 95064, USA
Peter Walter
Howard Hughes Medical Institute, University of California San Francisco, San Francisco, CA 94143, USA; Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA 94143, USA
Philippe Mourrain
Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA; INSERM 1024, Ecole Normale Supérieure, Paris, France
Yi Zuo
Department of Molecular, Cell and Developmental Biology, University of California Santa Cruz, Santa Cruz, CA 95064, USA; Corresponding author
Gordon X. Wang
Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA; Wu Tsai Neuroscience Institute, Stanford University, Stanford, CA 94305, USA; Corresponding author
Summary: Fragile X syndrome (FXS) is caused by the loss of fragile X messenger ribonucleoprotein (FMRP), a translational regulator that binds the transcripts of proteins involved in synaptic function and plasticity. Dysregulated protein synthesis is a central effect of FMRP loss, however, direct translational modulation has not been leveraged in the treatment of FXS. Thus, we examined the effect of the translational modulator integrated stress response inhibitor (ISRIB) in treating synaptic and behavioral symptoms of FXS. We show that FMRP loss dysregulates synaptic protein abundance, stabilizing dendritic spines through increased PSD-95 levels while preventing spine maturation through reduced glutamate receptor accumulation, thus leading to the formation of dense, immature dendritic spines, characteristic of FXS patients and Fmr1 knockout (KO) mice. ISRIB rescues these deficits and improves social recognition in Fmr1 KO mice. These findings highlight the therapeutic potential of targeting core translational mechanisms in FXS and neurodevelopmental disorders more broadly.
