Cell-type-specific disruption of cortico-striatal circuitry drives repetitive patterns of behavior in fragile X syndrome model mice
Francesco Longo,
Sameer Aryal,
Paul G. Anastasiades,
Marta Maltese,
Corey Baimel,
Federica Albanese,
Joanna Tabor,
Jeffrey D. Zhu,
Mauricio M. Oliveira,
Denise Gastaldo,
Claudia Bagni,
Emanuela Santini,
Nicolas X. Tritsch,
Adam G. Carter,
Eric Klann
Affiliations
Francesco Longo
Center for Neural Science, New York University, New York, NY 10003, USA; Institute for Neuroscience and Physiology, University of Gothenburg, 40530 Gothenburg, Sweden; Sackler Institute of Graduate Biomedical Sciences, NYU School of Medicine, New York, NY 10016, USA
Sameer Aryal
Center for Neural Science, New York University, New York, NY 10003, USA; NYU Neuroscience Institute, New York University Grossman School of Medicine, New York, NY 10016, USA
Paul G. Anastasiades
Center for Neural Science, New York University, New York, NY 10003, USA
Marta Maltese
Fresco Institute for Parkinson’s and Movement Disorders, New York University Langone Health, New York, NY 10016, USA; Department of Fundamental Neurosciences, University of Lausanne, 1005 Lausanne, Switzerland
Corey Baimel
Center for Neural Science, New York University, New York, NY 10003, USA
Federica Albanese
Center for Neural Science, New York University, New York, NY 10003, USA
Joanna Tabor
Center for Neural Science, New York University, New York, NY 10003, USA
Jeffrey D. Zhu
Center for Neural Science, New York University, New York, NY 10003, USA
Mauricio M. Oliveira
Center for Neural Science, New York University, New York, NY 10003, USA
Denise Gastaldo
Department of Biomedicine and Prevention, University of Rome “Tor Vergata,” 1005 Rome, Italy
Claudia Bagni
Department of Biomedicine and Prevention, University of Rome “Tor Vergata,” 1005 Rome, Italy
Emanuela Santini
Center for Neural Science, New York University, New York, NY 10003, USA; Department of Neuroscience, Biomedicum, Karolinska Institute, 171 77 Stockholm, Sweden
Nicolas X. Tritsch
NYU Neuroscience Institute, New York University Grossman School of Medicine, New York, NY 10016, USA; Fresco Institute for Parkinson’s and Movement Disorders, New York University Langone Health, New York, NY 10016, USA
Adam G. Carter
Center for Neural Science, New York University, New York, NY 10003, USA
Eric Klann
Center for Neural Science, New York University, New York, NY 10003, USA; NYU Neuroscience Institute, New York University Grossman School of Medicine, New York, NY 10016, USA; Corresponding author
Summary: Individuals with fragile X syndrome (FXS) are frequently diagnosed with autism spectrum disorder (ASD), including increased risk for restricted and repetitive behaviors (RRBs). Consistent with observations in humans, FXS model mice display distinct RRBs and hyperactivity that are consistent with dysfunctional cortico-striatal circuits, an area relatively unexplored in FXS. Using a multidisciplinary approach, we dissect the contribution of two populations of striatal medium spiny neurons (SPNs) in the expression of RRBs in FXS model mice. Here, we report that dysregulated protein synthesis at cortico-striatal synapses is a molecular culprit of the synaptic and ASD-associated motor phenotypes displayed by FXS model mice. Cell-type-specific translational profiling of the FXS mouse striatum reveals differentially translated mRNAs, providing critical information concerning potential therapeutic targets. Our findings uncover a cell-type-specific impact of the loss of fragile X messenger ribonucleoprotein (FMRP) on translation and the sequence of neuronal events in the striatum that drive RRBs in FXS.
