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.

Mercaldo, V., Vidimova, B., Gastaldo, D., Fernández, E., Lo, A.c., Cencelli, G., et al. (2023). Altered striatal actin dynamics drives behavioral inflexibility in a mouse model of fragile X syndrome. NEURON, 111(11), 1760-1775 [10.1016/j.neuron.2023.03.008].

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

Mercaldo, Valentina;Cencelli, Giulia;Pedini, Giorgia;De Rubeis, Silvia;Bagni, Claudia
2023-06-07

Abstract

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.
7-giu-2023
Pubblicato
Rilevanza internazionale
Articolo
Esperti anonimi
Settore BIOS-10/A - Biologia cellulare e applicata
English
Con Impact Factor ISI
FXS
Fmr1(y/−)
PSD
actin
actin dynamics
dendritic spines
flexibility
medium spiny neurons
striatum
synaptic proteome
Mercaldo, V., Vidimova, B., Gastaldo, D., Fernández, E., Lo, A.c., Cencelli, G., et al. (2023). Altered striatal actin dynamics drives behavioral inflexibility in a mouse model of fragile X syndrome. NEURON, 111(11), 1760-1775 [10.1016/j.neuron.2023.03.008].
Mercaldo, V; Vidimova, B; Gastaldo, D; Fernández, E; Lo, Ac; Cencelli, G; Pedini, G; De Rubeis, S; Longo, F; Klann, E; Smit, Ab; Grant, Sgn; Achsel, ...espandi
Articolo su rivista
File in questo prodotto:
File Dimensione Formato  
1-s2.0-S0896627323002040-main.pdf

solo utenti autorizzati

Tipologia: Versione Editoriale (PDF)
Licenza: Copyright dell'editore
Dimensione 2.7 MB
Formato Adobe PDF
2.7 MB Adobe PDF   Visualizza/Apri   Richiedi una copia

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/389094
Citazioni
  • ???jsp.display-item.citation.pmc??? 2
  • Scopus 11
  • ???jsp.display-item.citation.isi??? 7
social impact