Perineuronal nets as a novel therapeutic target for Fragile X syndrome

Fragile X syndrome (FXS) is one of the most common monogenetic form of intellectual disability and autism spectrum disorder. FXS commonly occurs due to a CGG repeat expansion-dependent hypermethylation of the Fragile X mental retardation (Fmr1) gene. To date, there are no approved therapies for the syndrome and only symptoms can be ameliorated. Fmr1KO mice replicate core FXS features, such as cortex GABAergic PV+ interneurons delayed development. Perineuronal nets (PNNs) are extracellular matrix assemblies crucial in neuronal physiology as they protect neurons and regulate synaptic currents. Furthermore, these specializations wrap PV+ interneurons regulating their maturation and the onset and closure of the critical period plasticity (CPP). Supporting evidences show that PNNs and PV+ GABAergic interneurons alterations may be involved in FXS, and that pharmacological reversion of their levels may rescue the pathological phenotype. Our works begins with a battery of analyses assessing the main alterations in diverse diagnostic behavioral symptom domains (repetitive behaviors, social interactions, verbal and nonverbal communication) in mice at different developmental stages (P20, P40 and P60). These results are then complemented with data retrieved from a custom method for a brain wide molecular analysis on P30 and P60 mice. Our results show a significant concomitant reduction in Fmr1KO PNNs and PV+ GABAergic interneurons, compared to WT counterparts, which may explain phenotypical FXS alterations such as compulsive behavior and social impairments. Therefore, our work paves the way to potential therapeutic interventions by regulation of PNN levels and presents a novel method for high-throughput molecular analysis of brain regions.