Fragile X syndrome (FXS) is caused by mutations in the FMR1 (fragile X mental retardation 1) gene. It is a significant form of heritable intellectual disability with comorbidity of other symptoms such as autism. Due to the lack of efficacious medication, repurposing the existing FDA-approved drugs may offer an opportunity to advance clinical intervention for FXS. Analysis of the whole-genome transcription signatures predicts new therapeutic action of vorinostat to correct pathological alterations associated with FXS. We further find that the administration of vorinostat restores object location memory and passive avoidance memory in the Fmr1 knockout (KO) mice. For the non-cognitive behavioral symptoms, vorinostat corrects the autism-associated alterations, including repetitive behavior and social interaction deficits. In the open field test, vorinostat dampens hyperactivity in the center area of the arena. Surprisingly, vorinostat does not affect the abnormally elevated protein synthesis in Fmr1 KO neurons, suggesting different outcomes from correcting behavioral symptoms and specific aspects of cellular pathology. Our data reveal the therapeutic effects of the FDA-approved drug vorinostat in a mouse model of FXS and advocate efficacy testing with human patients.
bioRxiv Subject Collection: Neuroscience