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bioRxiv · 10.64898/2026.06.12.731901

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

Maio, B.·Singh, A.·Hector, R.·Gadalla, K.·Selfridge, J.·Aria, F.·Louros, S. R.·Cobb, S. R.·Osterweil, E. K.
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Abstract

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. HighlightsO_LITRAP-seq reveals impaired activity-driven translation in Fmr1-/y inferior colliculus (IC) C_LIO_LIDeficient Npas4 induction reduces evoked inhibition in Fmr1-/y IC C_LIO_LIAAV9-FMR1 gene therapy normalizes translation and excitatory/inhibitory balance in Fmr1-/y IC C_LIO_LIAAV9-FMR1 gene therapy prevents audiogenic seizures in Fmr1-/y mice when administered neonatally or in adulthood C_LI

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Maio, B., Singh, A., Hector, R., Gadalla, K., Selfridge, J., Aria, F., Louros, S. R., Cobb, S. R., Osterweil, E. K.. 2026-06-16. FMR1 gene therapy restores activity-driven inhibition and prevents audiogenic seizures in Fmr1-/y mice. https://doi.org/10.64898/2026.06.12.731901

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