Article

Altered cerebellar connectivity in autism and cerebellar-mediated rescue of autism-related behaviors in mice

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Abstract

Cerebellar abnormalities, particularly in Right Crus I (RCrusI), are consistently reported in autism spectrum disorders (ASD). Although RCrusI is functionally connected with ASD-implicated circuits, the contribution of RCrusI dysfunction to ASD remains unclear. Here neuromodulation of RCrusI in neurotypical humans resulted in altered functional connectivity with the inferior parietal lobule, and children with ASD showed atypical functional connectivity in this circuit. Atypical RCrusI–inferior parietal lobule structural connectivity was also evident in the Purkinje neuron (PN) TscI ASD mouse model. Additionally, chemogenetically mediated inhibition of RCrusI PN activity in mice was sufficient to generate ASD-related social, repetitive, and restricted behaviors, while stimulation of RCrusI PNs rescued social impairment in the PN TscI ASD mouse model. Together, these studies reveal important roles for RCrusI in ASD-related behaviors. Further, the rescue of social behaviors in an ASD mouse model suggests that investigation of the therapeutic potential of cerebellar neuromodulation in ASD may be warranted.

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Acknowledgements

A.M.D. and C.J.S. acknowledge the support of P. Turkeltaub, C. Barrett, B. Drury, and S. Martin in neuroimaging data collection and analysis. All neurobehavioral experiments were performed at the Department of Psychiatry Rodent Behavioral Core, and the authors thank the Director for Core services, S. Birnbaum, for her assistance. The authors also appreciate assistance from the UT Southwestern Whole Brain Microscopy Facility, and from B. Nieman and L. Spencer Noakes for their work on the MRI sequence used. P.T.T. acknowledges support from the National Institute of Neurologic Disorders and Stroke of the NIH (K08 NS083733) the Child Neurology Foundation, the Tuberous Sclerosis Alliance, and the University of Texas Southwestern Medical Center Disease Oriented Clinical Scholar Award. C.J.S. acknowledges funding from the National Institute of Mental Health of the NIH (R15 MH106957), pilot research funds from the Department of Psychology, and institutional startup funds from American University. J.P.L. and J.E. acknowledge support from the Canadian Institute for Health Research (CIHR) and the Ontario Brain Institute (OBI). S.H.M. acknowledges support from Autism Speaks, the National Institute of Mental Health (R01 MH085328-09, R01 MH078160-07, and K01 MH109766), and the National Institute of Neurological Disorders and Stroke (R01 NS048527-08). E.K. acknowledges funding from National Institute of Drug Abuse T32 training grant (T32 DA007290-24).

Author information

Affiliations

  1. Department of Psychology and Center for Behavioral Neuroscience, American University, Washington, DC, USA

    • Catherine J. Stoodley
    •  & Anila M. D’Mello
  2. Toronto Mouse Imaging Centre, Hospital for Sick Kids, Toronto, Canada

    • Jacob Ellegood
    •  & Jason P. Lerch
  3. The Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, Texas, USA

    • Vikram Jakkamsetti
    • , Pei Liu
    • , Jennifer M. Gibson
    • , Elyza Kelly
    • , Fantao Meng
    • , Christopher A. Cano
    • , Juan M. Pascual
    •  & Peter T. Tsai
  4. Center for Neurodevelopmental and Imaging Research, Kennedy Krieger Institute, Baltimore, Maryland, USA

    • Mary Beth Nebel
    •  & Stewart H. Mostofsky

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Contributions

C.J.S. and P.T.T. formulated human experiments and analysis, while P.T.T. formulated experiments in mice. P.T.T., J.M.G., F.M., and C.A.C. carried out mouse experiments. A.M.D. and C.J.S. carried out human studies and analysis. J.E. and J.P.L. performed mouse MRI and analysis. C.J.S., A.M.D., M.B.N., and S.H.M. designed the human ASD analysis, and S.H.M. and M.B.N. provided the human ASD data. V.J., P.L., E.K., and J.M.P. performed electrophysiology experiments and analysis. C.J.S., A.M.D., and P.T.T. prepared the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Catherine J. Stoodley or Peter T. Tsai.

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