@article{c61f103c3f744548954c468a9be4f77b,
title = "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 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.",
keywords = "FXS, Fmr1, PSD, actin, actin dynamics, dendritic spines, flexibility, medium spiny neurons, striatum, synaptic proteome",
author = "Valentina Mercaldo and Barbora Vidimova and Denise Gastaldo and Esperanza Fern{\'a}ndez and Lo, {Adrian C.} and Giulia Cencelli and Giorgia Pedini and {De Rubeis}, Silvia and Francesco Longo and Eric Klann and Smit, {August B.} and Grant, {Seth G.N.} and Tilmann Achsel and Claudia Bagni",
note = "Funding Information: We are thankful to Annick Crevoisier for excellent administrative support and to Jonathan Royaert, Karin Jonkers, Joanna Viguie, Maellie Midroit, M{\'e}lanie Reinero, and Christiane Devenoges for technical assistance with the mouse colonies. We thank the VIB Proteomics Research Center for the mass spectrometry analysis. We are grateful to Kris Gevaert (Scientific advisor of the VIB Proteomics Research Center) and Manfredo Quadroni (Head proteomic Facility UNIL) for generating data and discussions. We thank Nathan Skene and Frank Koopmans for their scientific discussions and for sharing insights on the project. We thank Dr. Edward Ando and Mallory Wittwer from the EPFL Center for imaging for generating the scripts for the spine analysis. We thank Kris Dickson for the scientific discussion and proofreading of the manuscript. We are grateful to Leonardo Restivo, head of the department behavioral facility Neuro-BAU. This work was supported by the Department of Defense (W81XWH-15-1-0360, USA), first at VIB (Flemish Institute of Biotechnology) then at the University of Lausanne/Etat de Vaud; ERANET-NEURON Joint Transnational Research Projects on Sensory Disorders (2020-088), SNSF NCCR Synapsy 51NF40-158776 and SNSF 310030-182651; Associazione Italiana Sindrome X Fragile; and MUR-PRIN 201789LFKB and Fondazione Telethon GGP20137 to C.B. E.F. was supported by a Marie Curie FP7-PEOPLE-2010-IEF. S.D.R. was supported by the Seaver Beatrice and Samuel A. Seaver Foundation and a Distinguished Scholar Award from the Icahn School of Medicine at Mount Sinai. S.G.N.G. was supported by the European Research Council (ERC) under the European Union's Horizon 2020 Research and Innovation Programme (695568 SYNNOVATE), Simons Foundation Autism Research Initiative (529085), and the Wellcome Trust (Technology Development Grant 202932). Initial support was provided by VIB-KU Leuven Center for Brain & Disease Research. C.B. and T.A. designed the experiments with the contribution of all the authors. B.V. performed the image analysis for the spine morphology, actin dynamics in vitro and ex vivo, and viral efficiency. Purifications for mass spectrometry validation and synaptoneurosomal preparations were performed by D.G. and V.M. with the help of B.V. Western blots, primary neuronal cultures, biochemical assays, and IF on transfected primary neurons were performed and analyzed by D.G. and V.M. with the help of B.V. qPCR was performed by D.G. FMRP RNA immunoprecipitation assay and western blots were performed by G.P. and G.C. Purification for mass spectrometry analysis was performed by E.F. with the help of G.C. Viral injections and immunohistochemistry were performed by V.M. Behavioral experiments were performed by V.M. and A.C.L. with the help of D.G. and analyzed by V.M. and A.C.L. Evolutionary constraints and enrichment analyses were performed by S.D.R. R Script for mass spectrometry data analysis are from T.A. R scripts for behavioral analysis are from A.C.L. E.K. and F.L. contributed to the conceptualization of behavioral experiments. A.B.S. provided extensive analysis of the SynGO data and scientific inputs. S.G.N.G. and E.F. provided the PSD95FLAG mouse line and scientific input. V.M. B.V. D.G. T.A. and C.B. wrote the manuscript with the contribution of all the authors. C.B. supervised the project. All authors have read and approved the manuscript. A.B.S. participates in a company that holds shares of Synaptologics B.V. We support inclusive, diverse, and equitable conduct of research. Funding Information: We are thankful to Annick Crevoisier for excellent administrative support and to Jonathan Royaert, Karin Jonkers, Joanna Viguie, Maellie Midroit, M{\'e}lanie Reinero, and Christiane Devenoges for technical assistance with the mouse colonies. We thank the VIB Proteomics Research Center for the mass spectrometry analysis. We are grateful to Kris Gevaert (Scientific advisor of the VIB Proteomics Research Center) and Manfredo Quadroni (Head proteomic Facility UNIL) for generating data and discussions. We thank Nathan Skene and Frank Koopmans for their scientific discussions and for sharing insights on the project. We thank Dr. Edward Ando and Mallory Wittwer from the EPFL Center for imaging for generating the scripts for the spine analysis. We thank Kris Dickson for the scientific discussion and proofreading of the manuscript. We are grateful to Leonardo Restivo, head of the department behavioral facility Neuro-BAU. This work was supported by the Department of Defense (W81XWH-15-1-0360, USA), first at VIB (Flemish Institute of Biotechnology) then at the University of Lausanne/Etat de Vaud ; ERANET-NEURON Joint Transnational Research Projects on Sensory Disorders ( 2020-088 ), SNSF NCCR Synapsy 51NF40-158776 and SNSF 310030-182651 ; Associazione Italiana Sindrome X Fragile ; and MUR-PRIN 201789LFKB and Fondazione Telethon GGP20137 to C.B. E.F. was supported by a Marie Curie FP7-PEOPLE-2010-IEF . S.D.R. was supported by the Seaver Beatrice and Samuel A. Seaver Foundation and a Distinguished Scholar Award from the Icahn School of Medicine at Mount Sinai. S.G.N.G. was supported by the European Research Council (ERC) under the European Union{\textquoteright}s Horizon 2020 Research and Innovation Programme ( 695568 SYNNOVATE), Simons Foundation Autism Research Initiative ( 529085 ), and the Wellcome Trust (Technology Development Grant 202932 ). Initial support was provided by VIB-KU Leuven Center for Brain & Disease Research . Publisher Copyright: {\textcopyright} 2023 Elsevier Inc.",
year = "2023",
month = jun,
day = "7",
doi = "10.1016/j.neuron.2023.03.008",
language = "English (US)",
volume = "111",
pages = "1760--1775.e8",
journal = "Neuron",
issn = "0896-6273",
publisher = "Cell Press",
number = "11",
}