Altered striatal actin dynamics drives behavioral inflexibility in a mouse model of fragile X syndrome

The proteome of glutamatergic synapses is diverse across the mammalian brain and involved in neurode-velopmental disorders (NDDs). Among those is fragile X syndrome (FXS), an NDD caused by the absence of the functional RNA-binding protein FMRP. Here, we demonstrate how the brain region-specific composi-tion of postsynaptic density (PSD) contributes to FXS. In the striatum, the FXS mouse model shows an altered association of the PSD with the actin cytoskeleton, reflecting immature dendritic spine morphology and reduced synaptic actin dynamics. Enhancing actin turnover with constitutively active RAC1 amelio-rates these deficits. At the behavioral level, the FXS model displays striatal-driven inflexibility, a typical feature of FXS individuals, which is rescued by exogenous RAC1. Striatal ablation of Fmr1 is sufficient to recapitulate behavioral impairments observed in the FXS model. These results indicate that dysregula-tion of synaptic actin dynamics in the striatum, a region largely unexplored in FXS, contributes to the mani-festation of FXS behavioral phenotypes.