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

ABSTRACT: The proteome of glutamatergic synapses is diverse across the mammalian brain and involved in neurodevelopmental disorders (NDDs). Among those is Fragile X syndrome (FXS), an NDD caused by the dysfunctional RNA binding protein FMRP. Here we demonstrate how the brain region-specific composition of post-synaptic density (PSD) contributes to FXS. The FXS mouse model shows, in the striatum, 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 ameliorates these deficits. At the behavioral level, the FXS model displays striatal-driven inflexibility, a typical feature of FXS individuals, that is rescued by exogenous RAC1. Striatal ablation of Fmr1 is sufficient to recapitulate behavioral impairments observed in the FXS model. These results indicate that dysregulation of synaptic actin dynamics in the striatum, a region largely unexplored in FXS, contributes to the manifestation of FXS behavioral phenotypes.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain

DISEASE(S): Fragile X Syndrome

SUBMITTER: Tilmann Achsel  

LAB HEAD: Claudia Bagni

PROVIDER: PXD040331 | Pride | 2023-06-08

REPOSITORIES: Pride