FMR1 gene therapy restores activity-driven inhibition and prevents audiogenic seizures in Fmr1 -/y mice.

Fragile X syndrome (FXS) is a neurodevelopmental disorder associated with auditory hypersensitivity, circuit hyperexcitability, and seizures. Whether re-expression of the FMR1 gene and encoded Fragile X Messenger Ribonucleoprotein (FMRP) can restore sensory circuit dysfunction remains unclear. Here, we show that a viral AAV-FMR1 vector rescues audiogenic seizures in the Fmr1 -/y mouse model after both neonatal and adult delivery, indicating that auditory circuit dysfunction remains reversible. Local re-expression in the inferior colliculus (IC) is sufficient to reduce seizure susceptibility, identifying this region as a key site of FMRP-dependent circuit regulation. In the IC, Translating Ribosome Affinity Purification and RNA-seq (TRAP-seq) profiling reveals impaired induction of sound-evoked translation programs in Fmr1 -/y neurons, including those regulated by transcription factor Npas4. AAV-FMR1 restores a WT-like molecular response and normalizes unbalanced sound-evoked activation of VGLUT2+ excitatory neurons over VGAT+ inhibitory neurons in Fmr1 -/y IC. Together, these findings indicate altered translation of Npas4 in response to sound impairs recruitment of inhibition in the Fmr1 -/y IC, and this can be reversed with AAV-FMR1 administration. Moreover, the rescue of seizures after adult administration of AAV-FMR1 supports a gene therapy approach for FXS.