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

Fragile X syndrome (FXS) is characterized by sensory, social, and cognitive impairments. However, the specific ways in which the fragile X messenger ribonucleoprotein 1 (FMR1) deficiency disrupts sensory corticostriatal circuits and whether various FMR1 perturbations share common cellular mechanisms are not yet fully understood.

Researchers have now combined diffusion MRI in individuals with FXS and Fmr1-knockout mice with advanced calcium recording techniques, optogenetic manipulation, targeted gene expression in the somatosensory cortex, regional gene expression studies, and mitochondrial energetic state manipulation to unravel these mysteries.

Individuals with FXS showed disrupted sensory corticostriatal structural connectivity, and mouse models further pinpointed these abnormalities to the S1-striatal pathways. Specifically, Fmr1 deficiency hindered the activation of the S1-dorsomedial striatum (DMS) pathway during social interactions. By selectively manipulating these pathways, the researchers found that the S1-DMS dysfunction contributes significantly to the social and cognitive deficits observed in FXS patients.

Three patient-associated FMR1 variants (I234T, E329G, and R586Q) all converged on the same social behavioral deficits, which were ameliorated by activating the S1-DMS pathway. The team also discovered that there is a shared mitochondrial remodeling related to oxidative phosphorylation (OXPHOS) in both the S1 and DMS regions of the brain in Fmr1-deficient mice and those with the FMR1 variant models.

The systemic application of a mitochondria-targeted antioxidant called MitoQ alleviated novel-location-recognition, social-interaction, and social-novelty impairments in Fmr1-KO mice.

Furthermore, a technique known as Mitochondrial OptoEnergetic Activation (Mito-OptoEA) enhanced mitochondrial energetic state in the S1 region, leading to improvements in novel-location recognition and sociability in both Fmr1-KO and I234T models. In conclusion, these comprehensive findings provide a detailed framework highlighting how S1-DMS circuit dysfunction and convergent mitochondrial energetic abnormalities contribute to the social and cognitive phenotypes associated with FMR1-related Fragile X Syndrome.