The Cerebellum

, Volume 12, Issue 6, pp 950–955 | Cite as

Defining the Role of Cerebellar Purkinje Cells in Autism Spectrum Disorders

Journal Club


Understanding the contribution of cerebellar dysfunction to complex neurological diseases such as autism spectrum disorders (ASD) is an ongoing topic of investigation. In a recent paper, Tsai et al. (Nature 488:647–651, 2012) used a powerful combination of conditional mouse genetics, electrophysiology, behavioral tests, and pharmacological manipulations to address the role of Tuberous sclerosis complex 1 (Tsc1) in Purkinje cells and cerebellar function. The authors make the staggering discovery that morphological and electrophysiological defects in Purkinje cells are linked to system-wide ASD-like behavioral deficits. In this journal club, I discuss the major findings of this paper and critically assess the implications of this seminal work.


ASD Tsc1 Purkinje cells Behavior Synapses 


  1. 1.
    Kanner L. Autistic disturbances of affective contact. Nerv Child. 1943;2:217–50.Google Scholar
  2. 2.
    Fournier KA, Hass CJ, Naik SK, Lodha N, Cauraugh JH. Motor coordination in autism spectrum disorders: a synthesis and meta-analysis. J Autism Dev Disord. 2010;40(10):1227–40.PubMedCrossRefGoogle Scholar
  3. 3.
    Altman J, Bayer SA. Development of the cerebellar system: in relation to its evolution, structure, and functions. New York: CRC; 1996.Google Scholar
  4. 4.
    Sillitoe RVFY, Watson C. Cerebellum. In: Watson C, editor. PG, Puelles L, editor. The mouse nervous system: Elsevier Inc; 2012. p. 360–97.Google Scholar
  5. 5.
    Eluvathingal TJ, Behen ME, Chugani HT, Janisse J, Bernardi B, Chakraborty P, et al. Cerebellar lesions in tuberous sclerosis complex: neurobehavioral and neuroimaging correlates. J Child Neurol. 2006;21(10):846–51.PubMedCrossRefGoogle Scholar
  6. 6.
    Ertan G, Arulrajah S, Tekes A, Jordan L, Huisman TA. Cerebellar abnormality in children and young adults with tuberous sclerosis complex: MR and diffusion weighted imaging findings. J Neuroradiol. 2010;37(4):231–8.PubMedCrossRefGoogle Scholar
  7. 7.
    Weber AM, Egelhoff JC, McKellop JM, Franz DN. Autism and the cerebellum: evidence from tuberous sclerosis. J Autism Dev Disord. 2000;30(6):511–7.PubMedCrossRefGoogle Scholar
  8. 8.
    Tsai PT, Hull C, Chu Y, Greene-Colozzi E, Sadowski AR, Leech JM, et al. Autistic-like behaviour and cerebellar dysfunction in Purkinje cell Tsc1 mutant mice. Nature. 2012;488(7413):647–51.PubMedCrossRefGoogle Scholar
  9. 9.
    Kwiatkowski DJ, Zhang H, Bandura JL, Heiberger KM, Glogauer M, el-Hashemite N, 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. 2002;11(5):525–34.PubMedCrossRefGoogle Scholar
  10. 10.
    Barski JJ, Dethleffsen K, Meyer M. Cre recombinase expression in cerebellar Purkinje cells. Genesis. 2000;28(3–4):93–8.PubMedCrossRefGoogle Scholar
  11. 11.
    Tavazoie SF, Alvarez VA, Ridenour DA, Kwiatkowski DJ, Sabatini BL. Regulation of neuronal morphology and function by the tumor suppressors Tsc1 and Tsc2. Nat Neurosci. 2005;8(12):1727–34.PubMedCrossRefGoogle Scholar
  12. 12.
    Bauman ML, Kemper TL. Neuroanatomic observations of the brain in autism: a review and future directions. Int J Dev Neurosci. 2005;23(2–3):183–7.PubMedCrossRefGoogle Scholar
  13. 13.
    Fatemi SH, Aldinger KA, Ashwood P, Bauman ML, Blaha CD, Blatt GJ, et al. Consensus paper: pathological role of the cerebellum in autism. Cerebellum. 2012;11(3):777–807.PubMedCrossRefGoogle Scholar
  14. 14.
    Sajdel-Sulkowska EM, Xu M, Koibuchi N. Increase in cerebellar neurotrophin-3 and oxidative stress markers in autism. Cerebellum. 2009;8(3):366–72.PubMedCrossRefGoogle Scholar
  15. 15.
    Hutsler JJ, Zhang H. Increased dendritic spine densities on cortical projection neurons in autism spectrum disorders. Brain Res. 2010;1309:83–94.PubMedCrossRefGoogle Scholar
  16. 16.
    Meikle L, Pollizzi K, Egnor A, Kramvis I, Lane H, Sahin M, 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. 2008;28(21):5422–32.PubMedCrossRefGoogle Scholar
  17. 17.
    Meikle L, Talos DM, Onda H, Pollizzi K, Rotenberg A, Sahin M, 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. 2007;27(21):5546–58.PubMedCrossRefGoogle Scholar
  18. 18.
    Silverman JL, Yang M, Lord C, Crawley JN. Behavioural phenotyping assays for mouse models of autism. Nat Rev Neurosci. 2010;11(7):490–502.PubMedCrossRefGoogle Scholar
  19. 19.
    Tsai P, Sahin M. Mechanisms of neurocognitive dysfunction and therapeutic considerations in tuberous sclerosis complex. Curr Opin Neurol. 2011;24(2):106–13.PubMedCrossRefGoogle Scholar
  20. 20.
    Ehninger D, Han S, Shilyansky C, Zhou Y, Li W, Kwiatkowski DJ, et al. Reversal of learning deficits in a Tsc2+/− mouse model of tuberous sclerosis. Nat Med. 2008;14(8):843–8.PubMedCrossRefGoogle Scholar
  21. 21.
    Reith RM, McKenna J, Wu H, Hashmi SS, Cho SH, Dash PK, et al. Loss of Tsc2 in Purkinje cells is associated with autistic-like behavior in a mouse model of tuberous sclerosis complex. Neurobiol Dis. 2012;51:93–103.PubMedCrossRefGoogle Scholar
  22. 22.
    Musolino PL, Stoodley CJ, Schmahmann JD. Essential anatomy of the cerebellum and related structures. In: Boltshauser EaS, J., editor. Cerebellar disorders in children. London: McKeith; 2012. p. 456.Google Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Brain and Mind Research InstituteWeill Cornell Medical CollegeNew YorkUSA

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