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

Nature Neuroscience volume 20, pages 1744–1751 (2017)Cite this article

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An Author Correction to this article was published on 16 March 2018

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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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Fig. 1: FC and BOLD activation before and during tDCS administration in neurotypical adults.
Fig. 2: Chemogenetically mediated silencing of RCrusI results in increased activity in left parietal association cortex in mice.
Fig. 3: Altered connectivity between RCrusI and cortical association areas in ASD mouse model and in individuals with ASD.
Fig. 4: Chemogenetically mediated inhibition of RCrusI results in autism-related behaviors in mice.
Fig. 5: Chemogenetically mediated activation of RCrusI rescues social interaction impairment in PN Tsc1-mutant mice.

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  • 16 March 2018

    In the version of this article initially published, the Simons Foundation was missing from the list of sources of support to P.T.T. in the Acknowledgments. The error has been corrected in the HTML and PDF versions of the article.

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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, the Simons Foundation, 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).

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Authors and 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.

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Stoodley, C.J., D’Mello, A.M., Ellegood, J. et al. Altered cerebellar connectivity in autism and cerebellar-mediated rescue of autism-related behaviors in mice. Nat Neurosci 20, 1744–1751 (2017). https://doi.org/10.1038/s41593-017-0004-1

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