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


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.


  1. Prevalence. of autism spectrum disorders — Autism and Developmental Disabilities Monitoring Network, United States, 2006. MMWR Surveill. Summ. 58, 1–20 (2009)

  2. Bauman, M. L. & Kemper, T. L. Neuroanatomic observations of the brain in autism: a review and future directions. Int. J. Dev. Neurosci. 23, 183–187 (2005)

    Article  Google Scholar 

  3. Amaral, D. G., Schumann, C. M. & Nordahl, C. W. Neuroanatomy of autism. Trends Neurosci. 31, 137–145 (2008)

    Article  CAS  Google Scholar 

  4. Limperopoulos, C. et al. Does cerebellar injury in premature infants contribute to the high prevalence of long-term cognitive, learning, and behavioral disability in survivors? Pediatrics 120, 584–593 (2007)

    Article  Google Scholar 

  5. Jeste, S. S., Sahin, M., Bolton, P., Ploubidis, G. B. & Humphrey, A. Characterization of autism in young children with tuberous sclerosis complex. J. Child Neurol. 23, 520–525 (2008)

    Article  Google Scholar 

  6. Ertan, G., Arulrajah, S., Tekes, A., Jordan, L. & Huisman, T. A. Cerebellar abnormality in children and young adults with tuberous sclerosis complex: MR and diffusion weighted imaging findings. J. Neuroradiol. 37, 231–238 (2010)

    Article  CAS  Google Scholar 

  7. Weber, A. M., Egelhoff, J. C., McKellop, J. M. & Franz, D. N. Autism and the cerebellum: evidence from tuberous sclerosis. J. Autism Dev. Disord. 30, 511–517 (2000)

    Article  CAS  Google Scholar 

  8. Eluvathingal, T. J. et al. Cerebellar lesions in tuberous sclerosis complex: neurobehavioral and neuroimaging correlates. J. Child Neurol. 21, 846–851 (2006)

    Article  Google Scholar 

  9. Asano, E. et al. Autism in tuberous sclerosis complex is related to both cortical and subcortical dysfunction. Neurology 57, 1269–1277 (2001)

    Article  CAS  Google Scholar 

  10. Kwiatkowski, D. J. et al. A mouse model of TSC1 reveals sex-dependent lethality from liver hemangiomas, and up-regulation of p70S6 kinase activity in Tsc1 null cells. Hum. Mol. Genet. 11, 525–534 (2002)

    Article  CAS  Google Scholar 

  11. Barski, J. J., Dethleffsen, K. & Meyer, M. Cre recombinase expression in cerebellar Purkinje cells. Genesis 28, 93–98 (2000)

    Article  CAS  Google Scholar 

  12. Tsai, P. & Sahin, M. Mechanisms of neurocognitive dysfunction and therapeutic considerations in tuberous sclerosis complex. Curr. Opin. Neurol. 24, 106–113 (2011)

    Article  CAS  Google Scholar 

  13. Sajdel-Sulkowska, E. M., Xu, M. & Koibuchi, N. Increase in cerebellar neurotrophin-3 and oxidative stress markers in autism. Cerebellum 8, 366–372 (2009)

    Article  CAS  Google Scholar 

  14. Di Nardo, A. et al. Tuberous sclerosis complex activity is required to control neuronal stress responses in an mTOR-dependent manner. J. Neurosci. 29, 5926–5937 (2009)

    Article  CAS  Google Scholar 

  15. Reith, R. M., Way, S., McKenna, J., III, Haines, K. & Gambello, M. J. Loss of the tuberous sclerosis complex protein tuberin causes Purkinje cell degeneration. Neurobiol. Dis. 43, 113–122 (2011)

    Article  CAS  Google Scholar 

  16. Nie, D. et al. Tsc2-Rheb signaling regulates EphA-mediated axon guidance. Nature Neurosci. 13, 163–172 (2010)

    Article  CAS  Google Scholar 

  17. Tavazoie, S. F., Alvarez, V. A., Ridenour, D. A., Kwiatkowski, D. J. & Sabatini, B. L. Regulation of neuronal morphology and function by the tumor suppressors Tsc1 and Tsc2. Nature Neurosci. 8, 1727–1734 (2005)

    Article  CAS  Google Scholar 

  18. Meikle, L. et al. A mouse model of tuberous sclerosis: neuronal loss of Tsc1 causes dysplastic and ectopic neurons, reduced myelination, seizure activity, and limited survival. J. Neurosci. 27, 5546–5558 (2007)

    Article  CAS  Google Scholar 

  19. Meikle, L. et al. Response of a neuronal model of tuberous sclerosis to mammalian target of rapamycin (mTOR) inhibitors: effects on mTORC1 and Akt signaling lead to improved survival and function. J. Neurosci. 28, 5422–5432 (2008)

    Article  CAS  Google Scholar 

  20. Bateup, H. S., Takasaki, K. T., Saulnier, J. L., Denefrio, C. L. & Sabatini, B. L. Loss of Tsc1 In vivo impairs hippocampal mGluR-LTD and increases excitatory synaptic function. J. Neurosci. 31, 8862–8869 (2011)

    Article  CAS  Google Scholar 

  21. Choi, Y. J. et al. Tuberous sclerosis complex proteins control axon formation. Genes Dev. 22, 2485–2495 (2008)

    Article  CAS  Google Scholar 

  22. Young, D. M., Schenk, A. K., Yang, S. B., Jan, Y. N. & Jan, L. Y. Altered ultrasonic vocalizations in a tuberous sclerosis mouse model of autism. Proc. Natl Acad. Sci. USA 107, 11074–11079 (2010)

    Article  ADS  CAS  Google Scholar 

  23. Scattoni, M. L., Crawley, J. & Ricceri, L. Ultrasonic vocalizations: a tool for behavioural phenotyping of mouse models of neurodevelopmental disorders. Neurosci. Biobehav. Rev. 33, 508–515 (2009)

    Article  Google Scholar 

  24. De Zeeuw, C. I. et al. Spatiotemporal firing patterns in the cerebellum. Nature Rev. Neurosci. 12, 327–344 (2011)

    Article  CAS  Google Scholar 

  25. Ryu, Y. H. et al. Perfusion impairments in infantile autism on technetium-99m ethyl cysteinate dimer brain single-photon emission tomography: comparison with findings on magnetic resonance imaging. Eur. J. Nucl. Med. 26, 253–259 (1999)

    Article  CAS  Google Scholar 

  26. Zhou, J. et al. Pharmacological inhibition of mTORC1 suppresses anatomical, cellular, and behavioral abnormalities in neural-specific Pten knock-out mice. J. Neurosci. 29, 1773–1783 (2009)

    Article  CAS  Google Scholar 

  27. Insel, T. R. & Fernald, R. D. How the brain processes social information: searching for the social brain. Annu. Rev. Neurosci. 27, 697–722 (2004)

    Article  CAS  Google Scholar 

  28. Steinlin, M. Cerebellar disorders in childhood: cognitive problems. Cerebellum 7, 607–610 (2008)

    Article  Google Scholar 

  29. Müller, R. A. The study of autism as a distributed disorder. Ment. Retard. Dev. Disabil. Res. Rev. 13, 85–95 (2007)

    Article  Google Scholar 

  30. Schmahmann, J. D. Disorders of the cerebellum: ataxia, dysmetria of thought, and the cerebellar cognitive affective syndrome. J. Neuropsychiatry Clin. Neurosci. 16, 367–378 (2004)

    Article  Google Scholar 

  31. Yang, M., Silverman, J. L. & Crawley, J. N. Automated three-chambered social approach task for mice. Curr Protoc Neurosci Ch 8, Unit 8 26 (2011)

  32. Holmes, A. et al. Behavioral characterization of dopamine D5 receptor null mutant mice. Behav. Neurosci. 115, 1129–1144 (2001)

    Article  CAS  Google Scholar 

  33. Yang, M. & Crawley, J. N. Simple behavioral assessment of mouse olfaction. Curr Protoc. Neurosci. Ch 8, Unit 8 24 (2009)

  34. Silverman, J. L. et al. Sociability and motor functions in Shank1 mutant mice. Brain Res. 1380, 120–137 (2011)

    Article  CAS  Google Scholar 

  35. Bednar, I. et al. Selective nicotinic receptor consequences in APPSWE transgenic mice. Mol. Cell. Neurosci. 20, 354–365 (2002)

    Article  CAS  Google Scholar 

  36. Kurejova, M. et al. An improved behavioural assay demonstrates that ultrasound vocalizations constitute a reliable indicator of chronic cancer pain and neuropathic pain. Mol. Pain 6, 18 (2010)

    Article  Google Scholar 

  37. Buitrago, M. M., Schulz, J. B., Dichgans, J. & Luft, A. R. Short and long-term motor skill learning in an accelerated rotarod training paradigm. Neurobiol. Learn. Mem. 81, 211–216 (2004)

    Article  Google Scholar 

  38. Hull, C. & Regehr, W. G. Identification of an inhibitory circuit that regulates cerebellar Golgi cell activity. Neuron 73, 149–158 (2012)

    Article  CAS  Google Scholar 

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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 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.

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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).

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