Cerebellar contribution to autism-relevant behaviors in fragile X syndrome models

Cell Rep. 2023 Dec 26;42(12):113533. doi: 10.1016/j.celrep.2023.113533. Epub 2023 Dec 3.


Cerebellar dysfunction has been linked to autism spectrum disorders (ASDs). Although cerebellar pathology has been observed in individuals with fragile X syndrome (FXS) and in mouse models of the disorder, a cerebellar functional contribution to ASD-relevant behaviors in FXS has yet to be fully characterized. In this study, we demonstrate a critical cerebellar role for Fmr1 (fragile X messenger ribonucleoprotein 1) in ASD-relevant behaviors. First, we identify reduced social behaviors, sensory hypersensitivity, and cerebellar dysfunction, with loss of cerebellar Fmr1. We then demonstrate that cerebellar-specific expression of Fmr1 is sufficient to impact social, sensory, cerebellar dysfunction, and cerebro-cortical hyperexcitability phenotypes observed in global Fmr1 mutants. Moreover, we demonstrate that targeting the ASD-implicated cerebellar region Crus1 ameliorates behaviors in both cerebellar-specific and global Fmr1 mutants. Together, these results demonstrate a critical role for the cerebellar contribution to FXS-related behaviors, with implications for future therapeutic strategies.

Keywords: CP: Neuroscience; Purkinje cells; autism; cerebellum; fragile X; hyperexcitability; neurodevelopmental conditions; parietal cortex; sensory hypersensitivity; social behaviors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autism Spectrum Disorder*
  • Autistic Disorder* / genetics
  • Cerebellar Diseases*
  • Disease Models, Animal
  • Fragile X Mental Retardation Protein / genetics
  • Fragile X Mental Retardation Protein / metabolism
  • Fragile X Syndrome* / metabolism
  • Mice
  • Mice, Knockout


  • Fragile X Mental Retardation Protein
  • Fmr1 protein, mouse