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

Valentina Mercaldo, Barbora Vidimova, Denise Gastaldo, Esperanza Fernández, Adrian C Lo, Giulia Cencelli, Giorgia Pedini, Silvia De Rubeis, Francesco Longo, Eric Klann, August B Smit, Seth G N Grant, Tilmann Achsel, Claudia Bagni

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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 absence of the functional RNA-binding protein FMRP. Here, we demonstrate how the brain region-specific composition 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 ameliorates 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 dysregulation of synaptic actin dynamics in the striatum, a region largely unexplored in FXS, contributes to the manifestation of FXS behavioral phenotypes.

Original languageEnglish
Pages (from-to)1760-1775.e8
JournalNeuron
Volume111
Issue number11
Early online date29 Mar 2023
DOIs
Publication statusPublished - 7 Jun 2023

Keywords / Materials (for Non-textual outputs)

  • FXS
  • Fmr1
  • PSD
  • actin
  • actin dynamics
  • dendritic spines
  • flexibility
  • medium spiny neurons
  • striatum
  • synaptic proteome

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