FMR1 Perturbations Disrupt Sensory Corticostriatal Circuits and Mitochondrial Energetics in Fragile X Syndrome

Fragile X syndrome (FXS) features sensory, social, and cognitive dysfunction, but how fragile X messenger ribonucleoprotein 1 (FMR1) deficiency disrupts sensory corticostriatal circuitry and whether distinct FMR1 perturbations converge on shared cellular mechanisms remain incompletely defined. We integrated diffusion magnetic resonance imaging (MRI) in individuals with FXS and Fmr1-knockout (KO) mice with projection-defined calcium recording, bidirectional optogenetic manipulation, primary somatosensory cortex (S1)-targeted expression of three patient-associated FMR1 missense variants, regional transcriptomics, and optical manipulation of mitochondrial energetic state. Individuals with FXS exhibited disrupted sensory corticostriatal structural connectivity, with mouse analyses further localizing abnormalities to S1-striatal pathways. Fmr1 deficiency impaired recruitment of the S1-dorsomedial striatum (DMS) pathway during social interaction, and projection-specific manipulation demonstrated that S1-DMS dysfunction contributes to social and cognitive deficits. Three patient-associated FMR1 variants, I234T, E329G, and R586Q, converged on social behavioral deficits, which were improved by S1-DMS activation. Transcriptomic analyses revealed convergent oxidative phosphorylation (OXPHOS)-related mitochondrial remodeling in S1 and DMS across Fmr1 deficiency and variant models. Systemic treatment with the mitochondria-targeted antioxidant MitoQ attenuated novel-location-recognition, social-interaction, and social-novelty deficits in Fmr1-KO mice. Moreover, mt-EcGAPR-based Mitochondrial OptoEnergetic Activation (Mito-OptoEA) enhanced mitochondrial energetic state in S1 and improved novel-location recognition and sociability in both Fmr1-KO and I234T models. Together, these findings define a sensory corticostriatal circuit-metabolic framework for FXS in which S1-DMS circuit dysfunction and convergent mitochondrial energetic abnormalities contribute to FMR1-related social and cognitive phenotypes.