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Autistic-like behaviour and cerebellar dysfunction in Purkinje cell Tsc1 mutant mice

Nature volume 488, pages 647–651 (2012)Cite this article

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Abstract

Autism spectrum disorders (ASDs) are highly prevalent neurodevelopmental disorders1, but the underlying pathogenesis remains poorly understood. Recent studies have implicated the cerebellum in these disorders, with post-mortem studies in ASD patients showing cerebellar Purkinje cell (PC) loss2,3, and isolated cerebellar injury has been associated with a higher incidence of ASDs4. However, the extent of cerebellar contribution to the pathogenesis of ASDs remains unclear. Tuberous sclerosis complex (TSC) is a genetic disorder with high rates of comorbid ASDs5 that result from mutation of either TSC1 or TSC2, whose protein products dimerize and negatively regulate mammalian target of rapamycin (mTOR) signalling. TSC is an intriguing model to investigate the cerebellar contribution to the underlying pathogenesis of ASDs, as recent studies in TSC patients demonstrate cerebellar pathology6 and correlate cerebellar pathology with increased ASD symptomatology7,8. Functional imaging also shows that TSC patients with ASDs display hypermetabolism in deep cerebellar structures, compared to TSC patients without ASDs9. However, the roles of Tsc1 and the sequelae of Tsc1 dysfunction in the cerebellum have not been investigated so far. Here we show that both heterozygous and homozygous loss of Tsc1 in mouse cerebellar PCs results in autistic-like behaviours, including abnormal social interaction, repetitive behaviour and vocalizations, in addition to decreased PC excitability. Treatment of mutant mice with the mTOR inhibitor, rapamycin, prevented the pathological and behavioural deficits. These findings demonstrate new roles for Tsc1 in PC function and define a molecular basis for a cerebellar contribution to cognitive disorders such as autism.

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Figure 1: PC Tsc1 mutants display reduced PC numbers and abnormal PC morphology.
Figure 2: PC Tsc1 heterozygotes and mutants display autistic-like behaviours.
Figure 3: PC excitability is reduced in PC Tsc1 heterozygotes and mutants, but no significant difference is found in synaptic inputs to PCs.
Figure 4: Rapamycin treatment prevents pathological and behavioural abnormalities in PC Tsc1 mutant mice.

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Acknowledgements

We thank G. Corfas, M. Fagiolini, P. Rosenberg, S. Goldman and the Neurodevelopmental Behavioral Core of Boston Children’s Hospital for assistance with behavioural experiments. We are grateful to C. Walsh, L. Benowitz and members of the Sahin laboratory for critical reading of the manuscript, and to M. Gregas for advice regarding statistical analysis. P.T.T. received support from the Developmental Neurology Training grant (T32 NS007473), American Academy of Neurology, and the Nancy Lurie Marks Family Foundation. This work and M.S. are supported in part by the National Institutes of Health (NIH; grant R01 NS58956), the John Merck Scholars Fund, Autism Speaks, the Nancy Lurie Marks Family Foundation, Boston Children’s Hospital Translational Research Program, Manton Center for Orphan Disease Research and Boston Children’s Hospital Intellectual and Developmental Disabilities Research Center (grant P30 HD18655). J.N.C. is supported by the Intramural Research Program, National Institute of Mental Health. W.G.R. is supported by the NIH (grant R01NS032405) and the Simons Foundation (grant SFARI 232304). Y.X.C. is supported by the Howard Hughes Medical Institute Medical Research Fellowship.

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Author notes

  1. Court Hull and YunXiang Chu: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Neurology, The F.M. Kirby Neurobiology Center, Boston Children’s Hospital, Harvard Medical School, Boston, 02115, Massachusetts, USA

    Peter T. Tsai, Emily Greene-Colozzi, Abbey R. Sadowski, Jarrett M. Leech, Jason Steinberg & Mustafa Sahin

  2. Department of Neurobiology, Harvard Medical School, Boston, 02115, Massachusetts, USA

    Court Hull, YunXiang Chu & Wade G. Regehr

  3. Laboratory of Behavioral Neuroscience, Intramural Research Program, National Institute of Mental Health, Bethesda, 20892, Maryland, USA

    Jacqueline N. Crawley

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Contributions

Author Contributions P.T.T. and M.S. conceived and designed the experimental approach, performed experiments and prepared the manuscript. C.H. and Y.X.C. designed and performed cerebellar slice experiments and assisted in manuscript preparation. E.G.-C., A.R.S. and J.M.L. assisted with behavioural experiments and statistical analysis. J.S. contributed to experimental quantification. J.N.C. provided training for behavioural phenotyping and contributed to behavioural experimental design and analysis. W.G.R. and M.S. supervised the project, and contributed to experimental design and analysis.

Corresponding authors

Correspondence to Peter T. Tsai or Mustafa Sahin.

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Competing interests

M.S. has served as a consultant and site-PI for Novartis. He is also the PI for an investigator-initiated clinical trial partially funded by Novartis.

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Tsai, P., Hull, C., Chu, Y. et al. Autistic-like behaviour and cerebellar dysfunction in Purkinje cell Tsc1 mutant mice. Nature 488, 647–651 (2012). https://doi.org/10.1038/nature11310

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