Cerebellar contribution to autism-relevant behaviors in fragile X syndrome models
Jennifer M. Gibson,
Anthony Hernandez Vazquez,
Kunihiko Yamashiro,
Vikram Jakkamsetti,
Chongyu Ren,
Katherine Lei,
Brianne Dentel,
Juan M. Pascual,
Peter T. Tsai
Affiliations
Jennifer M. Gibson
Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Anthony Hernandez Vazquez
Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Kunihiko Yamashiro
Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Vikram Jakkamsetti
Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Chongyu Ren
Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Katherine Lei
Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Brianne Dentel
Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Juan M. Pascual
Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Peter T. Tsai
Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Corresponding author
Summary: 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.
