Skip to main content

Advertisement

SpringerLink
Log in

Consensus Paper: Pathological Role of the Cerebellum in Autism

  • Review
  • Published:
The Cerebellum Aims and scope Submit manuscript

Abstract

There has been significant advancement in various aspects of scientific knowledge concerning the role of cerebellum in the etiopathogenesis of autism. In the current consensus paper, we will observe the diversity of opinions regarding the involvement of this important site in the pathology of autism. Recent emergent findings in literature related to cerebellar involvement in autism are discussed, including: cerebellar pathology, cerebellar imaging and symptom expression in autism, cerebellar genetics, cerebellar immune function, oxidative stress and mitochondrial dysfunction, GABAergic and glutamatergic systems, cholinergic, dopaminergic, serotonergic, and oxytocin-related changes in autism, motor control and cognitive deficits, cerebellar coordination of movements and cognition, gene–environment interactions, therapeutics in autism, and relevant animal models of autism. Points of consensus include presence of abnormal cerebellar anatomy, abnormal neurotransmitter systems, oxidative stress, cerebellar motor and cognitive deficits, and neuroinflammation in subjects with autism. Undefined areas or areas requiring further investigation include lack of treatment options for core symptoms of autism, vermal hypoplasia, and other vermal abnormalities as a consistent feature of autism, mechanisms underlying cerebellar contributions to cognition, and unknown mechanisms underlying neuroinflammation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

References

  1. American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 4th ed (DSM-4). Washington, DC: APA; 1994.

    Google Scholar 

  2. Wassink TH, Brzustowicz LM, Bartlett CW, Szatmari P. The search for autism disease genes. Ment Retard Dev Disabil Res Rev. 2004;10:272–83.

    Article  PubMed  Google Scholar 

  3. Bauman ML, Kemper TL. Histoanatomic observations of the brain in early infantile autism. Neurology. 1985;35:866–74.

    Article  PubMed  CAS  Google Scholar 

  4. Arin DM, Bauman ML, Kemper TL. The distribution of Purkinje cell loss in the cerebellum in autism. Neurology. 1991;41(Suppl):307.

    Google Scholar 

  5. Bailey A, Luthert P, Dean A, Harding B, Janota I, Montgomery M, et al. A clinicopathological study of autism. Brain. 1998;121:889–905.

    Article  PubMed  Google Scholar 

  6. Whitney ER, Kemper TL, Bauman ML, Rosene DL, Blatt GJ. Cerebellar Purkinje cells are reduced in a subpopulation of autistic brains: a stereological experiment using calbindin-D28k. Cerebellum. 2008;7(3):406–16.

    Article  PubMed  CAS  Google Scholar 

  7. Bauman ML, Kemper TL, editors. The neurobiology of autism. Baltimore: Johns Hopkins University Press; 2005.

    Google Scholar 

  8. Courchesne E, Saitoh O, Yeung-Courchesne R, Press GA, Lincoln AJ, et al. Abnormality of cerebellar vermian lobules VI and VII in patients with infantile autism: identification of hypoplastic and hyperplastic subgroups by MR imaging. AJR. 1994;162:123–30.

    PubMed  CAS  Google Scholar 

  9. Whitney ER, Kemper TL, Rosene DL, Bauman ML, Blatt GJ. Density of cerebellar basket and stellate cells in autism: Evidence for a late developmental loss of Purkinje cells. J Neurosci Res. 2009;87:2245–54.

    Article  PubMed  CAS  Google Scholar 

  10. Holmes G, Stewart TG. On the connection of the inferior olives with the cerebellum in man. Brain. 1908;31:125–37.

    Article  Google Scholar 

  11. Greenfield JG, Greenfield JG. The spino-cerebellar degenerations. Springfield: CC Thomas; 1954.

    Google Scholar 

  12. DeBassio WA, Kemper TL, Knoefel JE. Coffin-Siris syndrome: neuropathological findings. Arch Neurol. 1985;42:350–3.

    Article  PubMed  CAS  Google Scholar 

  13. Kemper TL. The developmental neuropathology of autism. In: Blatt G, editor. The neurochemical basis of autism. New York: Springer; 2010. p. 69–82.

    Chapter  Google Scholar 

  14. Kemper TL, Bauman ML. Neuropathology of infantile autism. J Neuropath Exp Neurol. 1998;57:645–52.

    Article  PubMed  CAS  Google Scholar 

  15. Hazlett HC, Poe M, Gerig G, Smith RG, Provenzale J, Ross A, et al. Magnetic resonance imaging and head circumference study of brain size in autism: birth through age 2 years. Arch Gen Psychiatry. 2005;62:11366–76.

    Article  Google Scholar 

  16. Lainhart JE, Bigler ED, Bocian M, Coon H, Dinh E, Dawson G, et al. Head circumference and height in autism: a study by the collaborative program of excellence in autism. Am J Med Genet A. 2006;140:2257–74.

    PubMed  Google Scholar 

  17. Hardan AY, Libove RA, Keshavan MS, Melhem NM, Minshew NJ. A preliminary longitudinal magnetic resonance imaging study of brain volume and cortical thickness in autism. Biol Psychiatry. 2009;66:313–5.

    Article  Google Scholar 

  18. Schmahmann J. The cerebellum and cognition. International review of neurobiology, vol. 41. San Diego: Academic; 1997.

    Google Scholar 

  19. Schmahmann JD, Rosene DL, Pandya DN. Motor projections to the basis pontis in rhesus monkey. J Comp Neurol. 2004;478:248–68.

    Article  PubMed  Google Scholar 

  20. 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.

    Article  PubMed  Google Scholar 

  21. Minshew NJ, Sung K, Jones B, Furman JM. Underdevelopment of the postural control system in autism. Neurology. 2004;63(11):2056–61.

    Article  PubMed  Google Scholar 

  22. Ozonoff S, Young GS, Goldring S, Greiss-Hess L, Herrera AM, Steele J, et al. Gross motor development, movement abnormalities, and early identification of autism. J Autism Dev Disord. 2008;38:644–56.

    Article  PubMed  Google Scholar 

  23. Brettler SC, Fuchs AF, Ling L. Discharge patterns of cerebellar output neurons in the caudal fastigial nucleus during head-free gaze shifts in primates. Ann NY Acad Sci. 2003;1004:61–8.

    Article  PubMed  Google Scholar 

  24. Takarae Y, Minshew NJ, Luna B, Sweeney JA. Oculomotor abnormalities parallel cerebellar histopathology in autism. J Neurol Neurosurg Psychiatry. 2004;75(9):1359–61.

    Article  PubMed  CAS  Google Scholar 

  25. Nowinski CV, Minshew NJ, Luna B, Takarae Y, Sweeney JA. Oculomotor studies of cerebellar function in autism. Psychiatry Res. 2005;137(1–2):11–9.

    Article  PubMed  Google Scholar 

  26. Strick P, Dum R, Fiez J. Cerebellum and nonmotor function. Ann Rev Neurosci. 2009;32(1):413–34.

    Article  PubMed  CAS  Google Scholar 

  27. Ackermann H, Wildgruber D, Daum I, Grodd W. Does the cerebellum contribute to cognitive aspects of speech production? A functional magnetic resonance imaging (fMRI) study in humans. Neurosci Lett. 1998;247(2–3):187–90.

    Article  PubMed  CAS  Google Scholar 

  28. Tager-Flusberg H, Caronna E. Language disorders: autism and other pervasive developmental disorders. Pediatr Clin North Am. 2007;54(3):469–81.

    Article  PubMed  Google Scholar 

  29. Shriberg L, Paul R, Black L, van Santen J. The hypothesis of apraxia of speech in children with autism spectrum disorder. J Autism Dev Disord. 2011;41(4):405–26.

    Article  PubMed  Google Scholar 

  30. Steinlin M. The cerebellum in cognitive processes: supporting studies in children. Cerebellum. 2007;6:237–41.

    Article  PubMed  Google Scholar 

  31. Schmahmann JD, Sherman JC. The cerebellar cognitive affective syndrome. Brain. 1998;121(4):561–79.

    Article  PubMed  Google Scholar 

  32. Scott JA, Schumann CM, Goodlin-Jones BL, Amaral DG. A comprehensive volumetric analysis of the cerebellum in children and adolescents with autism spectrum disorder. Autism Res. 2009;2(5):246–57.

    Article  PubMed  Google Scholar 

  33. Ritvo ER, Freeman BJ, Scheibel AB, Duong T, Robinson H, Guthrie D, et al. Lower Purkinje cell counts in the cerebella of four autistic subjects: initial findings of the UCLA–NSAC autopsy research project. Am J Psychiatry. 1986;143(7):862–6.

    PubMed  CAS  Google Scholar 

  34. Courchesne E, Saitoh O, Townsend J, Yeung-Courchesne R, Press G, Lincoln A, et al. Cerebellar hypoplasia and hyperplasia in infantile autism. Lancet. 1994;343:63–4.

    Article  PubMed  CAS  Google Scholar 

  35. Ciesielski KT, Harris RJ, Hart BL, Pabst HF. Cerebellar hypoplasia and frontal lobe cognitive deficits in disorders of early childhood. Neuropsychologia. 1997;35(5):643–55.

    Article  PubMed  CAS  Google Scholar 

  36. Webb SJ, Sparks BF, Friedman SD, Shaw DW, Giedd J, Dawson G, et al. Cerebellar vermal volumes and behavioral correlates in children with autism spectrum disorder. Psychiatry Res. 2009;172(1):61–7.

    Article  PubMed  Google Scholar 

  37. Welsh JP, Yuen G, Placantonakis DG, Vu TQ, Haiss F, O’Hearn E, et al. Why do Purkinje cells die so easily after global brain ischemia? Aldolase C, EAAT4, and the cerebellar contribution to post-hypoxic myoclonus. Adv Neurol. 2002;89:331–59.

    PubMed  Google Scholar 

  38. Sarna JR, Hawkes R. Patterned Purkinje cell death in the cerebellum. Prog Neurobiol. 2003;70:473–507.

    Article  PubMed  CAS  Google Scholar 

  39. Welsh JP, Llinas R. Some organizing principles for the control of movement based on olivocerebellar physiology. Prog Brain Res. 1997;114:449–61.

    Article  PubMed  CAS  Google Scholar 

  40. Hawkes R, Colonnier M, Leclerc N. Monoclonal antibodies reveal sagittal banding in the rodent cerebellar cortex. Brain Res. 1985;333(2):359–65.

    Article  PubMed  CAS  Google Scholar 

  41. Hawkes R, Gravel C. The modular cerebellum. Prog Neurobiol. 1991;36(4):309–27.

    Article  PubMed  CAS  Google Scholar 

  42. Williams BL, Yaddanapudi K, Hornig M, Lipkin WI. Spatiotemporal analysis of Purkinje cell degeneration relative to parasagittal expression domains in a model of neonatal viral infection. J Virol. 2007;81:2675–87.

    Article  PubMed  CAS  Google Scholar 

  43. O’Hearn E, Molliver ME. The olivocerebellar projection mediates ibogaine-induced degeneration of Purkinje cells: a model of indirect, trans-synaptic excitotoxicity. J Neurosci. 1997;17:8828–41.

    PubMed  Google Scholar 

  44. Llinas R, Lang EJ, Welsh JP. The cerebellum, LTD, and memory: alternative views. Learn Mem. 1997;3:445–55.

    Article  PubMed  CAS  Google Scholar 

  45. Dager SR, Corrigan NM, Richards TL, Posse S. Research applications of magnetic resonance spectroscopy (MRS) to investigate psychiatric disorders. Top Magn Reson Imaging. 2008;19(2):81–96.

    Article  PubMed  Google Scholar 

  46. Dager SR, Corrigan NM, Richards TL, Shaw DWW. Brain chemistry: magnetic resonance spectroscopy. In: Amaral D, Dawson G, Geshwind D, editors. Autism spectrum disorders. England: Oxford University Press; 2011.

    Google Scholar 

  47. Welsh JP, Han VZ, Rossi D, Mohr C, Odagari M, Daunais J, et al. Bidirectional plasticity in the primate inferior olive induced by chronic ethanol intoxication and sustained abstinence. Proc Natl Acad Sci USA. 2011;108:10314–9.

    Article  PubMed  CAS  Google Scholar 

  48. Welsh JP, Lang EJ, Sugihara I, Llinas R. Dynamic organization of motor control within the olivocerebellar system. Nature. 1995;374:453–7.

    Article  PubMed  CAS  Google Scholar 

  49. Oristaglio J, Ghaffari M, Hyman West S, Welsh JP, Malone R. A sensory timing abnormality in autism revealed by classical eyeblink conditioning. Soc Neurosci Abstr. 2012; (in press).

  50. Gerwig M, Esser AC, Guberina H, Frings M, Kolb FP, Forsting M, et al. Trace eyeblink conditioning in patients with cerebellar degeneration: comparison of short and long trace intervals. Exp Brain Res. 2008;187:85–96.

    Article  PubMed  CAS  Google Scholar 

  51. Welsh JP, Ahn ES, Placantonakis DG. Is autism due to brain desynchronization? Int J Dev Neurosci. 2005;23:253–63.

    Article  PubMed  Google Scholar 

  52. Miles JH. Autism spectrum disorders—a genetics review. Genet Med. 2011;13(4):278–94.

    Article  PubMed  Google Scholar 

  53. Abrahams BS, Geschwind DH. Advances in autism genetics: on the threshold of a new neurobiology. Nat Rev Genet. 2008;9(5):341–55.

    Article  PubMed  CAS  Google Scholar 

  54. Banerjee-Basu S, Packer A. SFARI Gene: an evolving database for the autism research community. Dis Model Mech. 2010;3(3–4):133–5.

    Article  PubMed  Google Scholar 

  55. Schaaf CP, Zoghbi HY. Solving the autism puzzle a few pieces at a time. Neuron. 2011;70(5):806–8.

    Article  PubMed  CAS  Google Scholar 

  56. Bill BR, Geschwind DH. Genetic advances in autism: heterogeneity and convergence on shared pathways. Curr Opin Genet Dev. 2009;19(3):271–8.

    Article  PubMed  CAS  Google Scholar 

  57. Geschwind DH. Autism: many genes, common pathways? Cell. 2008;135(3):391–5.

    Article  PubMed  CAS  Google Scholar 

  58. Geschwind DH, Levitt P. Autism spectrum disorders: developmental disconnection syndromes. Curr Opin Neurobiol. 2007;17(1):103–11.

    Article  PubMed  CAS  Google Scholar 

  59. Kaufmann WE, Cooper KL, Mostofsky SH, Capone GT, Kates WR, Newschaffer CJ, et al. Specificity of cerebellar vermian abnormalities in autism: a quantitative magnetic resonance imaging study. J Child Neurol. 2003;18(7):463–70.

    Article  PubMed  Google Scholar 

  60. 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.

    Article  PubMed  Google Scholar 

  61. Moessner R, Marshall CR, Sutcliffe JS, Skaug J, Pinto D, Vincent J, et al. Contribution of SHANK3 mutations to autism spectrum disorder. Am J Hum Genet. 2007;81(6):1289–97.

    Article  PubMed  CAS  Google Scholar 

  62. Philippe A, Boddaert N, Vaivre-Douret L, Robel L, Danon-Boileau L, Malan V, et al. Neurobehavioral profile and brain imaging study of the 22q13.3 deletion syndrome in childhood. Pediatrics. 2008;122(2):e376–82.

    Article  PubMed  Google Scholar 

  63. Johnson MB, Kawasawa YI, Mason CE, Krsnik Z, Coppola G, Bogdanovic D, et al. Functional and evolutionary insights into human brain development through global transcriptome analysis. Neuron. 2009;62(4):494–509.

    Article  PubMed  CAS  Google Scholar 

  64. Alvarez Retuerto AI, Cantor RM, Gleeson JG, Ustaszewska A, Schackwitz WS, Pennacchio LA, et al. Association of common variants in the Joubert syndrome gene (AHI1) with autism. Hum Mol Genet. 2008;17(24):3887–96.

    Article  PubMed  CAS  Google Scholar 

  65. Voineagu I, Wang X, Johnston P, Lowe JK, Tian Y, Horvath S, et al. Transcriptomic analysis of autistic brain reveals convergent molecular pathology. Nature. 2011;474(7351):380–4.

    Article  PubMed  CAS  Google Scholar 

  66. Descipio C, Schneider L, Young TL, Wasserman N, Yaeger D, Lu F, et al. Subtelomeric deletions of chromosome 6p: molecular and cytogenetic characterization of three new cases with phenotypic overlap with Ritscher-Schinzel (3 C) syndrome. Am J Med Genet A. 2005;134A(1):3–11.

    Article  PubMed  Google Scholar 

  67. Miles JH, Hillman RE. Value of a clinical morphology examination in autism. Am J Med Genet. 2000;91(4):245–53.

    Article  PubMed  CAS  Google Scholar 

  68. Cheh MA, Millonig JH, Roselli LM, Ming X, Jacobsen E, Kamdar S, et al. En2 knockout mice display neurobehavioral and neurochemical alterations relevant to autism spectrum disorder. Brain Res. 2006;1116(1):166–76.

    Article  PubMed  CAS  Google Scholar 

  69. Ieraci A, Forni PE, Ponzetto C. Viable hypomorphic signaling mutant of the Met receptor reveals a role for hepatocyte growth factor in postnatal cerebellar development. Proc Natl Acad Sci U S A. 2002;99(23):15200–5.

    Article  PubMed  CAS  Google Scholar 

  70. Fatemi SH, Reutiman TJ, Folsom TD, Thuras PD. GABA(A) receptor downregulation in brains of subjects with autism. J Autism Dev Disord. 2009;39(2):223–30.

    Article  PubMed  Google Scholar 

  71. DeLorey TM, Sahbaie P, Hashemi E, Homanics GE, Clark JD. Gabrb3 gene deficient mice exhibit impaired social and exploratory behaviors, deficits in non-selective attention and hypoplasia of cerebellar vermal lobules: a potential model of autism spectrum disorder. Behav Brain Res. 2008;187(2):207–20.

    Article  PubMed  CAS  Google Scholar 

  72. Careaga M, Van de Water J, Ashwood P. Immune dysfunction in autism: a pathway to treatment. Neurotherapeutics. 2010;7(3):283–92.

    Article  PubMed  CAS  Google Scholar 

  73. Vargas DL, Nascimbene C, Krishnan C, Zimmerman AW, Pardo CA. Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann Neurol. 2005;57(1):67–81.

    Article  PubMed  CAS  Google Scholar 

  74. Chez MG, Dowling T, Patel PB, Khanna P, Kominsky M. Elevation of tumor necrosis factor-alpha in cerebrospinal fluid of autistic children. Pediatr Neurol. 2007;36(6):361–5.

    Article  PubMed  Google Scholar 

  75. Li X, Chauhan A, Sheikh AM, Patil S, Chauhan V, Li XM, et al. Elevated immune response in the brain of autistic patients. J Neuroimmunol. 2009;207:111–6.

    Article  PubMed  CAS  Google Scholar 

  76. Wei H, Zou H, Sheikh AM, Malik M, Dobkin C, Brown WT, et al. IL-6 is increased in the cerebellum of autistic brain and alters neural cell adhesion, migration and synaptic formation. J Neuroinflammation. 2011;8:52.

    Article  PubMed  CAS  Google Scholar 

  77. Garbett K, Ebert PJ, Mitchell A, Lintas C, Manzi B, Mirnics K, et al. Immune transcriptome alterations in the temporal cortex of subjects with autism. Neurobiol Dis. 2008;30:303–11.

    Article  PubMed  CAS  Google Scholar 

  78. Cabanlit M, Wills S, Goines P, Ashwood P, Van de Water J. Brain-specific autoantibodies in the plasma of subjects with autistic spectrum disorder. Ann NY Acad Sci. 2007;1107:92–103.

    Article  PubMed  CAS  Google Scholar 

  79. Goines P, Haapanen L, Boyce R, Duncanson P, Braunschweig D, Delwiche L, et al. Autoantibodies to cerebellum in children with autism associate with behavior. Brain Behav Immun. 2011;25:514–23.

    Article  PubMed  CAS  Google Scholar 

  80. Wills S, Cabanlit M, Bennett J, Ashwood P, Amaral DG, Van de Water J. Detection of autoantibodies to neural cells of the cerebellum in the plasma of subjects with autism spectrum disorders. Brain Behav Immun. 2009;23(1):64–74.

    Article  PubMed  CAS  Google Scholar 

  81. Wills S, Rossi CC, Bennett J, Cerdeño VM, Ashwood P, Amaral DG, et al. Further characterization of autoantibodies to GABAergic neurons in the central nervous system produced by a subset of children with autism. Mol Autism. 2011;2:5.

    Article  PubMed  Google Scholar 

  82. Ashwood P, Krakowiak P, Hertz-Picciotto I, Hansen R, Pessah I, Van de Water J. Elevated plasma cytokines in autism spectrum disorders provide evidence of immune dysfunction and are associated with impaired behavioral outcome. Brain Behav Immun. 2011;25:40–5.

    Article  PubMed  CAS  Google Scholar 

  83. Ashwood P, Anthony A, Torrente F, Wakefield AJ. Spontaneous mucosal lymphocyte cytokine profiles in children with autism and gastrointestinal symptoms: mucosal immune activation and reduced counter regulatory interleukin-10. J Clin Immunol. 2004;24:664–73.

    Article  PubMed  CAS  Google Scholar 

  84. Ashwood P, Wakefield AJ. Immune activation of peripheral blood and mucosal CD3+ lymphocyte cytokine profiles in children with autism and gastrointestinal symptoms. J Neuroimmunol. 2006;173:126–34.

    Article  PubMed  CAS  Google Scholar 

  85. Heuer L, Ashwood P, Goines P, Krakowiak P, Hertz-Picciotto I, Hansen R, et al. Reduced levels of immunoglobulin in children with autism correlates with behavioral symptoms. Autism Research. 2008;1:275–83.

    Article  PubMed  Google Scholar 

  86. Enstrom A, Krakowiak P, Onore C, Pessah IN, Hertz-Picciotto I, Hansen RL, et al. Increased IgG4 levels in children with autism disorder. Brain Behav Immun. 2009;23:389–95.

    Article  PubMed  CAS  Google Scholar 

  87. Corbett BA, Kantor AB, Schulman H, Walker WL, Lit L, Ashwood P, et al. A proteomic study of serum from children with autism showing differential expression of apolipoproteins and complement proteins. Mol Psychiatry. 2007;12:292–306.

    PubMed  CAS  Google Scholar 

  88. Ashwood P, Krakowiak P, Hertz-Picciotto I, Hansen R, Pessah I, Van de Water J. Associations of impaired behaviors with elevated plasma chemokines in autism spectrum disorders. J Neuroimmunol. 2011;232(1–2):196–201.

    Article  PubMed  CAS  Google Scholar 

  89. Enstrom AM, Lit L, Onore CE, Gregg JP, Hansen R, Pessah IN, et al. Altered gene expression and function of peripheral blood natural killer cells in children with autism. Brain Behav Immun. 2009;23:124–33.

    Article  PubMed  CAS  Google Scholar 

  90. Ashwood P, Schauer J, Pessah IN, Van de Water J. Preliminary evidence of the in vitro effects of BDE-47 on innate immune responses in children with autism spectrum disorders. J Neuroimmunol. 2009;208:149–53.

    Article  CAS  Google Scholar 

  91. Enstrom AM, Onore CE, Van de Water JA, Ashwood P. Differential monocyte responses to TLR ligands in children with autism spectrum disorders. Brain Behav Immun. 2010;24:64–71.

    Article  PubMed  CAS  Google Scholar 

  92. Ashwood P, Corbett BA, Kantor A, Schulman H, Van de Water J, Amaral DG. In search of cellular immunophenotypes in the blood of children with autism. PLoS One. 2011;6:e19299.

    Article  PubMed  CAS  Google Scholar 

  93. Ashwood P, Krakowiak P, Hertz-Picciotto I, Hansen R, Pessah IN, Van de Water J. Altered T cell responses in children with autism. Brain Behav Immun. 2011;25(5):840–9.

    Article  PubMed  CAS  Google Scholar 

  94. Ashwood P, Enstrom A, Krakowiak P, Hertz-Picciotto I, Hansen RL, Croen LA, et al. Decreased transforming growth factor beta1 in autism: a potential link between immune dysregulation and impairment in clinical behavioral outcomes. J Neuroimmunol. 2008;204:149–53.

    Article  PubMed  CAS  Google Scholar 

  95. Onore C, Enstrom A, Krakowiak P, Hertz-Picciotto I, Hansen R, Van de Water J, et al. Decreased cellular IL-23 but not IL-17 production in children with autism spectrum disorders. J Neuroimmunol. 2009;216:126–34.

    Article  PubMed  CAS  Google Scholar 

  96. Chauhan A, Chauhan V, Brown WT, editors. Autism: oxidative stress, inflammation and immune abnormalities. Boca Raton: CRC Press; 2009.

    Google Scholar 

  97. Deth R, Muratore C, Benzecry J, Power-Charnitsky VA, Waly M. How environmental and genetic factors combine to cause autism: a redox/methylation hypothesis. Neurotoxicology. 2008;29:190–201.

    Article  PubMed  CAS  Google Scholar 

  98. Chauhan A, Chauhan V. Oxidative stress in autism. Pathophysiology. 2006;13:171–81.

    Article  PubMed  CAS  Google Scholar 

  99. Kern JK, Jones AM. Evidence of toxicity, oxidative stress, and neuronal insult in autism. J Toxicol Environ Health B Crit Rev. 2006;9:485–99.

    Article  PubMed  CAS  Google Scholar 

  100. Wells PG, McCallum GP, Chen CS, Henderson JT, Lee CJ, Perstin J, et al. Oxidative stress in developmental origins of disease: teratogenesis, neurodevelopmental deficits, and cancer. Toxicol Sci. 2009;108:4–18.

    Article  PubMed  CAS  Google Scholar 

  101. Kinney DK, Munir KM, Crowley DJ, Miller AM. Prenatal stress and risk for autism. Neurosci Biobehav Rev. 2008;32:1519–32.

    Article  PubMed  Google Scholar 

  102. Kolevzon A, Gross R, Reichenberg A. Prenatal and perinatal risk factors for autism: a review and integration of findings. Arch Pediatr Adolesc Med. 2007;161:326–33.

    Article  PubMed  Google Scholar 

  103. Chauhan A, Gu F, Essa MM, Wegiel J, Kaur K, Brown WT, et al. Brain region-specific deficit in mitochondrial electron transport chain complexes in children with autism. J Neurochem. 2011;117:209–20.

    Article  PubMed  CAS  Google Scholar 

  104. Muthaiyah B, Essa MM, Chauhan V, Brown WT, Wegiel J, Chauhan A. Increased lipid peroxidation in cerebellum and temporal cortex of brain in autism. J Neurochem. 2009;108 Suppl 1:73.

    Google Scholar 

  105. Chauhan A, Audhya T, Chauhan V. Increased DNA oxidation in the cerebellum, frontal and temporal cortex of brain in autism. Transactions of the American Society for Neurochemistry. Windermere: American Society for Neurochemistry; 2011. p. 81.

    Google Scholar 

  106. Sajdel-Sulkowska EM, Xu M, Koibuchi N. Increase in cerebellar neurotrophin-3 and oxidative stress markers in autism. Cerebellum. 2009;8:366–72.

    Article  PubMed  CAS  Google Scholar 

  107. Chauhan A, Essa MM, Muthaiyah B, Brown WT,Wegiel J, Chauhan V. Increased protein oxidation in cerebellum, frontal and temporal cortex in autism. International Meeting for Autism Research (Abstract), May 2010.

  108. Sajdel-Sulkowska EM, Lipinski B, Windom H, Audhya T, McGinnis W. Oxidative stress in autism: elevated cerebellar 3-nitrotyrosine levels. Am J Biochem Biotech. 2008;4:73–84.

    Article  CAS  Google Scholar 

  109. Evans TA, Siedlak SL, Lu L, Fu X, Wang Z, McGinnis WR, et al. The autistic phenotype exhibits a remarkably localized modification of brain protein by products of free radical-induced lipid oxidation. Am J Biochem Biotech. 2008;4:61–72.

    Article  CAS  Google Scholar 

  110. López-Hurtado E, Prieto JJ. A microscopic study of language-related cortex in autism. Am J Biochem Biotech. 2008;4:130–45.

    Article  Google Scholar 

  111. Chauhan A, Audhya T, Chauhan V. Brain region-specific glutathione redox imbalance and increased DNA oxidation in autism. J Neurochem. 2011;118(suppl 1):217.

    Google Scholar 

  112. Ji L, Chauhan A, Brown WT, Chauhan V. Increased activities of Na+/K+-ATPase and Ca2+/Mg2+-ATPase in the frontal cortex and cerebellum of autistic individuals. Life Sci. 2009;85:788–93.

    Article  PubMed  CAS  Google Scholar 

  113. Lenaz G. The mitochondrial production of reactive oxygen species: mechanisms and implications in human pathology. IUBMB Life. 2001;52:159–64.

    Article  PubMed  CAS  Google Scholar 

  114. Rossignol DA, Frye RE. Mitochondrial dysfunction in autism spectrum disorders: a systematic review and meta-analysis. Mol Psychiatry. 2011; (in press), doi:10.1038/mp.2010.136.

  115. Courchesne E. New evidence of cerebellar and brainstem hypoplasia in autistic infants, children and adolescents: the MR imaging study by Hashimoto and colleagues. J Autism Dev Disord. 1995;25:19–22.

    Article  PubMed  CAS  Google Scholar 

  116. Zilbovicius M, Boddaert N, Belin P, Poline JB, Remy P, Mangin JF, et al. Temporal lobe dysfunction in childhood autism: a PET study. Positron emission tomography. Am J Psychiatry. 2000;157:1988–93.

    Article  PubMed  CAS  Google Scholar 

  117. Schmitz C, Rezaie P. The neuropathology of autism: where do we stand? Neuropathol Appl Neurobiol. 2008;34:4–11.

    PubMed  CAS  Google Scholar 

  118. Bauman ML, Kemper TL. Neuroanatomic observations of the brain in autism: a review and future directions. Int J Dev Neurosci. 2005;23:183–7.

    Article  PubMed  Google Scholar 

  119. Casanova MF. The neuropathology of autism. Brain Pathol. 2007;17:422–33.

    Article  PubMed  Google Scholar 

  120. Palmen SJ, van Engeland H, Hof PR, Schmitz C. Neuropathological findings in autism. Brain. 2004;127:2572–83.

    Article  PubMed  Google Scholar 

  121. Wegiel J, Wisniewski T, Chauhan A, Chauhan V, Kuchna I, Nowicki K, et al. Type, topology, and sequelae of neuropathological changes shaping clinical phenotype of autism. In: Chauhan A, Chauhan V, Brown WT, editors. Autism: oxidative stress, inflammation and immune abnormalities. Boca Raton: CRC Press; 2009. p. 1–34.

    Chapter  Google Scholar 

  122. Fatemi SH, Halt AR, Stary JM, Kanodia R, Schulz SC, Realmuto GR. Glutamic acid decarboxylase 65 and 67 kDa proteins are reduced in autistic parietal and cerebellar cortices. Biol Psychiatry. 2002;52(8):805–10.

    Article  PubMed  CAS  Google Scholar 

  123. Fatemi SH, Folsom TD. Dysregulation of fragile X mental retardation protein and metabotropic glutamate receptor 5 in superior frontal cortex of individuals with autism: a postmortem brain study. Mol Autism. 2011;2:6.

    Article  PubMed  CAS  Google Scholar 

  124. Fatemi SH, Folsom TD, Reutiman TJ, Thuras PD. Expression of GABA(B) receptors is altered in brains of subjects with autism. Cerebellum. 2009;8:64–9.

    Article  PubMed  CAS  Google Scholar 

  125. Yip J, Soghomonian JJ, Blatt GJ. Decreased GAD67 mRNA levels in cerebellar Purkinje cells in autism: pathophysiological implications. Acta Neuropathol. 2007;113(5):559–68.

    Article  PubMed  CAS  Google Scholar 

  126. Fatemi SH, Stary JM, Halt AR, Realmuto GR. Dysregulation of Reelin and Bcl-2 proteins in autistic cerebellum. J Autism Dev Disord. 2001;31:529–35.

    Article  PubMed  CAS  Google Scholar 

  127. Yip J, Soghomonian JJ, Blatt GJ. Decreased GAD65 mRNA levels in select subpopulations of neurons in the cerebellar dentate nuclei in autism: an in situ hybridization study. Autism Res. 2009;2(1):50–9.

    Article  PubMed  Google Scholar 

  128. Fatemi SH, Folsom TD, Kneeland RE, Liesch SB. Metabotropic glutamate receptor 5 upregulation in children with autism is associated with underexpression of both Fragile X mental retardation protein and GABA A receptor beta 3 in adults with Autism. Anat Rec. 2011;294(10):1635–45.

    Article  CAS  Google Scholar 

  129. Blatt GJ, Fitzgerald CM, Guptill JT, Booker AB, Kemper TL, Bauman ML. Density and distribution of hippocampal neurotransmitter receptors in autism: an autoradiographic study. J Autism Dev Disord. 2001;31(6):537–43.

    Article  PubMed  CAS  Google Scholar 

  130. Fatemi SH, Reutiman TJ, Folsom TD, Rooney PJ, Patel DH, Thuras PD. mRNA and protein levels for GABAAalpha4, alpha5, beta1, and GABABR1 receptors are altered in brains from subjects with autism. J Autism Dev Disord. 2010;40:743–50.

    Article  PubMed  Google Scholar 

  131. Oblak AL, Gibbs TT, Blatt GJ. Decreased GABAA receptors and benzodiazepine binding sites in the anterior cingulate cortex in autism. Autism Res. 2009;2(4):205–19.

    Article  PubMed  CAS  Google Scholar 

  132. Oblak AL, Gibbs TT, Blatt GJ. Decreased GABA(B) receptors in the cingulate cortex and fusiform gyrus in autism. J Neurochem. 2010;114(5):1414–23.

    PubMed  CAS  Google Scholar 

  133. Pesold C, Pisu MG, Impagnatiello F, Uzunov DP, Caruncho HJ. Reelin is preferentially expressed in neurons synthesizing gamma-aminobutyric acid in cortex and hippocampus of adult rats. Proc Natl Acad Sci. 1998;95:3221–6.

    Article  PubMed  CAS  Google Scholar 

  134. Sinagra M, Gonzalez Campo C, Verrier D, Moustié O, Manzoni OJ, Chavis P. Glutamatergic cerebellar granule neurons synthesize and secrete reelin in vitro. Neuron Glia Biol. 2008;4:189–96.

    Article  PubMed  Google Scholar 

  135. Quattrocchi CC, Wannenes F, Persico AM, Ciafré SA, D’Arcangelo G, Farace MG, et al. Reelin is a serine protease of the extracellular matrix. J Biol Chem. 2002;277:303–9.

    Article  PubMed  CAS  Google Scholar 

  136. Weeber EJ, Beffert U, Jones C, Christian JM, Forster E, Sweatt JD, et al. Reelin and ApoE receptors cooperate to enhance hippocampal synaptic plasticity and learning. J Biol Chem. 2002;277:39944–52.

    Article  PubMed  CAS  Google Scholar 

  137. Forster E, Tielsch A, Saum B, Weiss KH, Johanssen C, Graus-Porta D, et al. Reelin, Disabled 1, and beta 1 integrins are required for the formation of the radial glial scaffold in the hippocampus. Proc Natl Acad Sci. 2002;99:13178–83.

    Article  PubMed  CAS  Google Scholar 

  138. Nullmeier S, Panther P, Dobrowolny H, Frotscher M, Zhao S, Schwegler H, et al. Region-specific alteration of GABAergic markers in the brain of heterozygous reeler mice. Eur J Neurosci. 2011;33:689–98.

    Article  PubMed  CAS  Google Scholar 

  139. Cremer CM, Lubke JH, Palomero-Gallagher N, Zilles K. Laminar distribution of neurotransmitter receptors in different reeler mouse brain regions. Brain Struct Funct. 2011;216:201–18.

    Article  PubMed  CAS  Google Scholar 

  140. Kelemenova S, Schmidtova E, Ficek A, Celec P, Kubranska A, Ostatnikova D. Polymorphisms of candidate genes in Slovak autistic patients. Psychiatr Genet. 2010;20:137–9.

    Article  PubMed  Google Scholar 

  141. Persico AM, D’Agruma L, Maiorano N, Totaro A, Militerni R, Bravaccio C, et al. Reelin gene alleles and haplotypes as a factor predisposing to autistic disorder. Mol Psychiatry. 2001;6:150–9.

    Article  PubMed  CAS  Google Scholar 

  142. Fatemi SH, Snow AV, Stary JM, Araghi-Niknam M, Reutiman TJ, Lee S, et al. Reelin signaling is impaired in autism. Biol Psychiatry. 2005;57(7):777–87.

    Article  PubMed  CAS  Google Scholar 

  143. Fatemi SH, Stary JM, Egan EA. Reduced blood levels of reelin as a vulnerability factor in pathophysiology of autistic disorder. Cell Mol Neurobiol. 2002;22:139–52.

    Article  PubMed  CAS  Google Scholar 

  144. D’Arcangelo G, Homayouni R, Keshvara L, Rice DS, Sheldon M, Curran T. Reelin is a ligand for lipoprotein receptors. Neuron. 1999;24:471–9.

    Article  PubMed  Google Scholar 

  145. Hiesberger T, Trommsdorff M, Howell BW, Goffinet A, Mumby MC, Cooper JA, et al. Direct binding of Reelin to VLDL receptor and ApoE receptor 2 induces tyrosine phosphorylation of disabled-1 and modulates tau phosphorylation. Neuron. 1999;24:481–9.

    Article  PubMed  CAS  Google Scholar 

  146. Dulabon L, Olson EC, Taglienti MG, Eisenhuth S, McGrath B, Walsh CA, et al. Reelin binds alpha3beta1 integrin and inhibits neuronal migration. Neuron. 2000;27:33–44.

    Article  PubMed  CAS  Google Scholar 

  147. Strasser V, Fasching D, Hauser C, Mayer H, Bock HH, Hiesberger T, et al. Receptor clustering is involved in Reelin signaling. Mol Cell Biol. 2004;24:1378–86.

    Article  PubMed  CAS  Google Scholar 

  148. Mattson MP. Glutamate and neurotrophic factors in neuronal plasticity and disease. Ann N Y Acad Sci. 2008;1144:97–112.

    Article  PubMed  CAS  Google Scholar 

  149. Hoehn-Saric R, McLeod DR, Glowa JR. The effects NMDA receptor blockade on the acquisition of a conditioned emotional response. Biol Psychiatry. 1991;30:170–6.

    Article  PubMed  CAS  Google Scholar 

  150. Lisman J. Long-term potentiation: outstanding questions and attempted synthesis. Philos Trans R Soc Lond B Biol Sci. 2003;358:829–42.

    Article  PubMed  CAS  Google Scholar 

  151. Silverman JM, Buxbaum JD, Ramoz N, Schmeidler J, Reichenberg A, Hollander E, et al. Autism-related routines and rituals associated with a mitochondrial aspartate/glutamate carrier SLC25A12 polymorphism. Am J Med Genet B Neuropsychiatr Genet. 2008;147:408–10.

    PubMed  Google Scholar 

  152. Strutz-Seebohm N, Korniychuk G, Schwarz R, Baltaev R, Ureche ON, Mack AF, et al. Functional significance of the kainate receptor GluR6(M836I) mutation that is linked to autism. Cell Physiol Biochem. 2006;18:287–94.

    Article  PubMed  CAS  Google Scholar 

  153. Kim SA, Kim JH, Park M, Cho IH, Yoo HJ. Family-based association study between GRIK2 polymorphisms and autism spectrum disorders in Korean trios. Neurosci Res. 2007;58:332–5.

    Article  PubMed  CAS  Google Scholar 

  154. Purcell AE, Jeon OH, Zimmerman AW, Blue ME, Pevsner J. Postmortem brain abnormalities of the glutamate neurotransmitter system in autism. Neurology. 2001;57:1618–28.

    Article  PubMed  CAS  Google Scholar 

  155. Lepagnol-Bestel AM, Maussion G, Boda B, Cardona A, Iwayama Y, Delezoide AL, et al. SLC25A12 expression is associated with neurite outgrowth and is upregulated in the prefrontal cortex of autistic subjects. Mol Psychiatry. 2008;13:385–97.

    Article  PubMed  CAS  Google Scholar 

  156. Demark JL, Feldman MA, Holden JJ. Behavioral relationship between autism and fragile X syndrome. Am J Ment Retard. 2003;108:314–26.

    Article  PubMed  Google Scholar 

  157. De Rubeis S, Bagni C. Fragile X mental retardation protein control of neuronal mRNA metabolism: insights into mRNA stability. Mol Cell Neurosci. 2010;43:43–50.

    Article  PubMed  CAS  Google Scholar 

  158. Bassell GJ, Warren ST. Fragile X Syndrome: loss of local mRNA regulation alters synaptic development and function. Neuron. 2008;60:201–14.

    Article  PubMed  CAS  Google Scholar 

  159. Muddashetty RS, Kelić S, Gross C, Xu M, Bassell GJ. Dysregulated metabotropic glutamate receptor-dependent translation of AMPA receptor and postsynaptic density-95 mRNAs at synapses in a mouse model of fragile x syndrome. J Neurosci. 2007;27:5338–48.

    Article  PubMed  CAS  Google Scholar 

  160. Bear MF, Huber KM, Warren ST. The mGluR theory of fragile X mental retardation. Trends Neurosci. 2004;27:370–7.

    Article  PubMed  CAS  Google Scholar 

  161. Hashimoto H, Fukui K, Noto T, Nakajima T, Kato N. Distribution of vasopressin and oxytocin in rat brain. Endocrinol Jpn. 1985;32(1):89–97.

    Article  PubMed  CAS  Google Scholar 

  162. Kirsch P, Meyer-Lindenberg A. Oxytocin and autism. In: Blatt Gene J, editor. The neurochemical basis of autism: from molecules to minicolumns. New York: Springer; 2010. p. 163–73.

    Chapter  Google Scholar 

  163. Ferguson JN, Aldag JM, Insel TR, Young LJ. Oxytocin in the medial amygdala is essential for social recognition in the mouse. J Neurosci. 2001;21:8278–85.

    PubMed  CAS  Google Scholar 

  164. McCarthy MM, McDonald CH, Brooks PJ, Goldman D. An anxiolytic action of oxytocin is enhanced by estrogen in the mouse. Physiol Behav. 1996;60:1209–15.

    Article  PubMed  CAS  Google Scholar 

  165. Insel TR, Young LJ. The neurobiology of attachment. Nat Rev Neurosci. 2001;2:129–36.

    Article  PubMed  CAS  Google Scholar 

  166. Winslow JT, Insel TR. Neuroendocrine basis of social recognition. Curr Opin Neurobiol. 2004;14:248–53.

    Article  PubMed  CAS  Google Scholar 

  167. Liu W, Pappas GD, Carter CS. Oxytocin receptors in brain cortical regions are reduced in the haploinsufficient (+/−) reeler mice. Neurol Res. 2005;27(4):339–45.

    Article  PubMed  CAS  Google Scholar 

  168. Baskerville TA, Douglas AJ. Dopamine and oxytocin interactions underlying behaviors: potential contributions to behavioral disorders. CNS Neurosci Ther. 2010;16(3):e92–e123.

    Article  PubMed  CAS  Google Scholar 

  169. Hollander E, Novotny S, Hanratty M, Yaffe R, DeCaria CM, Aronowitz BR, et al. Oxytocin infusion reduces repetitive behaviors in adults with autistic and Asperger’s disorders. Neuropsychopharm. 2003;28:193–8.

    Article  CAS  Google Scholar 

  170. Hollander E, Bartz J, Chaplin W, Phillips A, Sumner J, Soorya L, et al. Oxytocin increases retention of social cognition in autism. Biol Psychiatry. 2007;61:498–503.

    Article  PubMed  CAS  Google Scholar 

  171. Bartz JA, Hollander E. Oxytocin and experimental therapeutics in autism spectrum disorders. Prog Brain Res. 2008;170:451–62.

    Article  PubMed  CAS  Google Scholar 

  172. Lee M, Martin-Ruiz C, Graham A, Court J, Jaros E, Perry R, et al. Nicotinic receptor abnormalities in the cerebellar cortex in autism. Brain. 2002;125(Pt 7):1483–95.

    Article  PubMed  CAS  Google Scholar 

  173. Martin-Ruiz CM, Lee M, Perry RH, Baumann M, Court JA, Perry EK. Molecular analysis of nicotinic receptor expression in autism. Brain Res Mol Brain Res. 2004;123(1–2):81–90.

    Article  PubMed  CAS  Google Scholar 

  174. Deutsch SI, Urbano MR, Neumann SA, Burket JA, Katz E. Cholinergic abnormalities in autism: is there a rationale for selective nicotinic agonist interventions? Clin Neuropharmacol. 2010;33(3):114–20.

    Article  PubMed  CAS  Google Scholar 

  175. Lippiello PM. Nicotinic cholinergic antagonists: a novel approach for the treatment of autism. Med Hypotheses. 2006;66(5):985–90.

    Article  PubMed  CAS  Google Scholar 

  176. Blatt GJ, VanSluytman G, Marcon RG. Decreased density of 3[H]AFDX-labeled cholinergic M2 receptors in the medial accessory olive in autism. Soc Neurosci. 2004;34:116.12.

    Google Scholar 

  177. Armstrong DD, Assman S, Kinney HC. Early developmental changes in the chemoarchitecture of the human inferior olive: a review. J Neuropathol Exp Neurol. 1999;58:1–11.

    Article  PubMed  CAS  Google Scholar 

  178. Kolasiewicz W, Kuter K, Nowak P, Pastuszka A, Ossowska K. Lesion of the cerebellar noradrenergic innervation enhances the harmaline-induced tremor in rats. Cerebellum. 2011;10(2):267–80.

    Article  PubMed  Google Scholar 

  179. Rogers TD, Dickson PE, Heck DH, Goldowitz D, Mittleman G, Blaha CD. Connecting the dots of the cerebro-cerebellar role in cognitive function: neuronal pathways for cerebellar modulation of dopamine release in the prefrontal cortex. Synapse. 2011;65(11):1204–12.

    Article  PubMed  CAS  Google Scholar 

  180. Mittleman G, Goldowitz D, Heck DH, Blaha CD. Cerebellar modulation of frontal cortex dopamine efflux in mice: relevance to autism and schizophrenia. Synapse. 2008;62(7):544–50.

    Article  PubMed  CAS  Google Scholar 

  181. Crandall JE, McCarthy DM, Araki KY, Sims JR, Ren J-Q, Bhide PG. Dopamine receptor activation modulates GABA neuron migration from the basal forebrain to the cerebral cortex. J Neurosci. 2007;27(14):3813–22.

    Article  PubMed  CAS  Google Scholar 

  182. Nakamura K, Sekine Y, Ouchi Y, Tsujii M, Yoshikawa E, Futatsubashi M, et al. Brain serotonin and dopamine transporter bindings in adults with high-functioning autism. Arch Gen Psychiatry. 2010;67(1):58–68.

    Article  Google Scholar 

  183. Buitelaar JK, Willemsen-Swinkels SH. Medication treatment in subjects with autistic spectrum disorders. Eur Child Adolesc Psychiatry. 2000;9(1):185–97.

    Article  Google Scholar 

  184. Kish SJ, Furukawa Y, Chang L-J, Tong J, Ginovart N, Wilson A, et al. Regional distribution of serotonin transporter protein in post-mortem human brain: is the cerebellum a SERT-free brain region? Nucl Med Biol. 2005;32(2):123–8.

    Article  PubMed  CAS  Google Scholar 

  185. Marazziti D. A further support to the hypothesis of a link between serotonin, autism, and the cerebellum. Biol Psychiatry. 2002;52(2):143.

    Article  PubMed  Google Scholar 

  186. Makkonen I, Riikonen R, Kokki H, Airaksinen MM, Kuikka JT. Serotonin and dopamine transporter binding in children with autism determined by SPECT. Dev Med Child Neurol. 2008;50(8):593–7.

    Article  PubMed  Google Scholar 

  187. Azmitia EC, Singh JS, Whitaker-Azmitia PM. Increased serotonin axons (immunoreactive to 5-HT transporter) in postmortem brains from young autism donors. Neuropharm. 2011;60:1347–54.

    Article  CAS  Google Scholar 

  188. Williams K, Wheeler DM, Silove N, Hazell P. Selective serotonin reuptake inhibitors (SSRIs) for autism spectrum disorders (ASD). Cochrane Database Syst Rev. 2010;4(8):CD004677.

    Google Scholar 

  189. Stanfield AC, McIntosh AM, Spencer MD, Philip R, Gaur S, Lawrie SM. Towards a neuroanatomy of autism: a systematic review and meta-analysis of structural magnetic resonance imaging studies. Eur Psychiatry. 2008;23(4):289–99.

    Article  PubMed  Google Scholar 

  190. Abrahams BS, Geschwind DH. Connecting genes to brain in the autism spectrum disorders. Arch Neurol. 2010;67(4):395–9.

    Article  PubMed  Google Scholar 

  191. Leiner HC, Leiner AL, Dow RS. Does the cerebellum contribute to mental skills? Behav Neurosci. 1986;100(4):443–54.

    Article  PubMed  CAS  Google Scholar 

  192. Stoodley CJ, Schmahmann JD. Functional topography in the human cerebellum: a meta-analysis of neuroimaging studies. NeuroImage. 2009;44(2):489–501.

    Article  PubMed  Google Scholar 

  193. Middleton FA, Strick PL. Cerebellar output channels. Int Rev Neurobiol. 1997;41:61–82.

    Article  PubMed  CAS  Google Scholar 

  194. Bloedel JR, Bantli H. A spinal action of the dentate nucleus mediated by descending systems originating in the brain stem. Brain Res. 1978;153(3):602–7.

    Article  PubMed  CAS  Google Scholar 

  195. Kanner L. Autistic disturbances of affective contact. The Nervous Child. 1943;2:217–50.

    Google Scholar 

  196. Asperger H. ‘Autistic psychopathy’ in childhood. In: Frith U, editor. Autism and Asperger syndrome. New York: Cambridge University Press; 1991. p. 37–92.

    Chapter  Google Scholar 

  197. Molloy CA, Dietrich KN, Bhattacharya A. Postural stability in children with autism spectrum disorder. J Autism Dev Disord. 2003;33(6):643–52.

    Article  PubMed  Google Scholar 

  198. Freitag CM, Kleser C, Schneider M, von Gontard A. Quantitative assessment of neuromotor function in adolescents with high functioning autism and Asperger Syndrome. J Autism Dev Disord. 2007;37(5):948–59.

    Article  PubMed  Google Scholar 

  199. Mostofsky SH, Powell SK, Simmonds DJ, Goldberg MC, Caffo B, Pekar JJ. Decreased connectivity and cerebellar activity in autism during motor task performance. Brain. 2009;132(9):2413–25.

    Article  PubMed  Google Scholar 

  200. Allen G, Courchesne E. Differential effects of developmental cerebellar abnormality on cognitive and motor functions in the cerebellum: an fMRI study of autism. Am J Psychiatry. 2003;160(2):262–73.

    Article  PubMed  Google Scholar 

  201. Muller RA, Pierce K, Ambrose JB, Allen G, Courchesne E. Atypical patterns of cerebral motor activation in autism: a functional magnetic resonance study. Biol Psychiatry. 2001;49(8):665–76.

    Article  PubMed  CAS  Google Scholar 

  202. Takarae Y, Minshew NJ, Luna B, Krisky CM, Sweeney JA. Pursuit eye movement deficits in autism. Brain. 2004;127(Pt 12):2584–94.

    Article  PubMed  Google Scholar 

  203. Takarae Y, Minshew NJ, Luna B, Sweeney JA. Atypical involvement of frontostriatal systems during sensorimotor control in autism. Psychiatry Res. 2007;156(2):117–27.

    Article  PubMed  Google Scholar 

  204. Mosconi MW, Kay M, D’Cruz AM, Guter S, Kapur K, Macmillan C, et al. Neurobehavioral abnormalities in first-degree relatives of individuals with autism. Arch Gen Psychiatry. 2010;67(8):830–40.

    Article  PubMed  Google Scholar 

  205. Williams DL, Goldstein G, Minshew NJ. The profile of memory function in children with autism. Neuropsychology. 2006;20(1):21–9.

    Article  PubMed  Google Scholar 

  206. Townsend J, Courchesne E, Covington J, Westerfield M, Harris NS, Lyden P, et al. Spatial attention deficits in patients with acquired or developmental cerebellar abnormality. J Neurosci. 1999;19(13):5632–43.

    PubMed  CAS  Google Scholar 

  207. Herbert MR, Harris GJ, Adrien KT, Ziegler DA, Makris N, Kennedy DN, et al. Abnormal asymmetry in language association cortex in autism. Ann Neurol. 2002;52(5):588–96.

    Article  PubMed  Google Scholar 

  208. Hodge SM, Makris N, Kennedy DN, Caviness Jr VS, Howard J, McGrath L, et al. Cerebellum, language, and cognition in autism and specific language impairment. J Autism Dev Disord. 2010;40(3):300–16.

    Article  PubMed  Google Scholar 

  209. Stoodley CJ. The cerebellum and cognition: evidence from functional imaging studies. Cerebellum. 2012; (in press).

  210. Gordon N. The cerebellum and cognition. Eur J Paediatr Neurol. 2007;11:232–4.

    Article  PubMed  Google Scholar 

  211. Kelly RM, Strick PL. Cerebellar loops with motor cortex and prefrontal cortex of a nonhuman primate. J Neurosci. 2003;23:8432–44.

    PubMed  CAS  Google Scholar 

  212. Middleton FA, Strick PL. Cerebellar projections to the prefrontal cortex of the primate. J Neurosci. 2001;21:700–12.

    PubMed  CAS  Google Scholar 

  213. Courchesne E. Brainstem, cerebellar and limbic neuroanatomical abnormalities in autism. Curr Opin Neurobiol. 1997;7:269–78.

    Article  PubMed  CAS  Google Scholar 

  214. Llinas R. I of the vortex. From neurons to self. Cambridge: MIT Press; 2002.

    Google Scholar 

  215. Sasaki K, Gemba H. Cerebro-cerebellar interactions: for fast and stable timing of voluntary movement. In: Mano N, Hamada I, DeLong MR, editors. Role of the cerebellum and basal ganglia in voluntary movement. Amsterdam: Elsevier; 1993. p. 41–50.

    Google Scholar 

  216. Ivry RB, Keele SW, Diener HC. Dissociation of the lateral and medial cerebellum in movement timing and movement execution. Exp Brain Res. 1988;73:167–80.

    Article  PubMed  CAS  Google Scholar 

  217. Braitenberg V. Is the cerebellar cortex a biological clock in the millisecond range? In: Fox CA, Snider RS, editors. Progress in Brain Research. Vol.25. The Cerebellum. Amsterdam: Elsevier; 1967. p. 334–46.

    Google Scholar 

  218. Yuste R, MacLean JN, Smith J, Lansner A. The cortex as a central pattern generator. Nat Rev Neurosci. 2005;6:477–83.

    Article  PubMed  CAS  Google Scholar 

  219. Ayzenshtat I, Meirovithz E, Edelman H, Werner-Reiss U, Bienenstock E, Abeles M, et al. Precise spatiotemporal patterns among visual cortical areas and their relation to visual stimulus processing. J Neurosci. 2010;30:11232–45.

    Article  PubMed  CAS  Google Scholar 

  220. Ben-Shaul Y, Drori R, Asher I, Stark E, Nadasdy Z, Abeles M. Neuronal activity in motor cortical areas reflects the sequential context of movement. J Neurophysiol. 2004;91:1748–1762. 7.

    Article  PubMed  Google Scholar 

  221. Prut Y, Vaadia E, Bergman H, Haalman I, Slovin H, Abeles M. Spatiotemporal structure of cortical activity: properties and behavioral relevance. J Neurophysiol. 1998;79:2857–74.

    PubMed  CAS  Google Scholar 

  222. Braitenberg V, Atwood RP. Morphological observations on the cerebellar cortex. J Comp Neurol. 1958;109:1–33.

    Article  PubMed  CAS  Google Scholar 

  223. Heck DH. Rat cerebellar cortex in vitro responds specifically to moving stimuli. Neurosci Lett. 1993;157:95–8.

    Article  PubMed  CAS  Google Scholar 

  224. Heck DH. Sequential input to guinea pig cerebellar cortex in vitro strongly affects Purkinje cells via parallel fibers. Naturwissenschaften. 1995;82:201–3.

    Article  PubMed  CAS  Google Scholar 

  225. Braitenberg V, Heck DH, Sultan F. The detection and generation of sequences as a key to cerebellar function. Experiments and theory. Behav Brain Sci. 1997;20:229–45.

    PubMed  CAS  Google Scholar 

  226. Molinari M, Chiricozzi FR, Clausi S, Tedesco AM, De Lisa M, Leggio MG. Cerebellum and detection of sequences, from perception to cognition. Cerebellum. 2008;7:611–5.

    Article  PubMed  Google Scholar 

  227. Andreasen NC, Paradiso S, O’Leary DS. “Cognitive dysmetria” as an integrative theory of schizophrenia: a dysfunction in cortical-subcortical-cerebellar circuitry? Schizophr. Bull. 1998;24:203–18.

    CAS  Google Scholar 

  228. Courchesne E, Yeung-Courchesne R, Press GA, Hesselink JR, Jernigan TL. Hypoplasia of cerebellar vermal lobules VI and VII in autism. N Engl J Med. 1988;318:1349–54.

    Article  PubMed  CAS  Google Scholar 

  229. Bauman ML. Microscopic neuroanatomic abnormalities in autism. Pediatrics. 1991;87:791–6.

    PubMed  CAS  Google Scholar 

  230. Persico AM, Bourgeron T. Searching for ways out of the autism maze: genetic, epigenetic and environmental clues. Trends Neurosci. 2006;29:349–58.

    Article  PubMed  CAS  Google Scholar 

  231. Rice D, Barone Jr S. Critical periods of vulnerability for the developing nervous system: evidence from humans and animal models. Environ Health Perspect. 2000;108 Suppl 3:511–33.

    PubMed  Google Scholar 

  232. Fombonne E. Epidemiology of autistic disorder and other pervasive developmental disorders. J Clin Psychiatry. 2005;66 Suppl 10:3–8.

    PubMed  Google Scholar 

  233. Landrigan PJ. What causes autism? Exploring the environmental contribution. Curr Opin Pediatr. 2010;22:219–25.

    Article  PubMed  Google Scholar 

  234. Bailey A, Le Couteur A, Gottesman I, Bolton P, Simonoff E, Yuzda E, et al. Autism as a strongly genetic disorder: evidence from a British twin study. Psychol Med. 1995;25:63–77.

    Article  PubMed  CAS  Google Scholar 

  235. Hallmayer J, Cleveland S, Torres A, Phillips J, Cohen B, Torigoe T, et al. Genetic heritability and shared environmental factors among twin pairs with autism. Arch Gen Psychiatry. 2011;68(11):1095–102.

    Article  PubMed  Google Scholar 

  236. Gaita L, Manzi B, Sacco R, Lintas C, Altieri L, Lombardi F, et al. Decreased serum arylesterase activity in autism spectrum disorders. Psychiatry Res. 2010;180:105–13.

    Article  PubMed  CAS  Google Scholar 

  237. Paşca SP, Nemeş B, Vlase L, Gagyi CE, Dronca E, Miu AC, et al. High levels of homocysteine and low serum paraoxonase 1 arylesterase activity in children with autism. Life Sci. 2006;78:2244–8.

    Article  PubMed  CAS  Google Scholar 

  238. Lugli G, Krueger JM, Davis JM, Persico AM, Keller F, Smalheiser NR. Methodological factors influencing measurement and processing of plasma reelin in humans. BMC Biochem. 2003;4:9.

    Article  PubMed  Google Scholar 

  239. D’Amelio M, Ricci I, Sacco R, Liu X, D'Agruma L, Muscarella LA, et al. Paraoxonase gene variants are associated with autism in North America, but not in Italy: possible regional specificity in gene-environment interactions. Mol Psychiatry. 2005;10:1006–16.

    Article  PubMed  CAS  Google Scholar 

  240. Persico AM, Levitt P, Pimenta AF. Polymorphic GGC repeat differentially regulates human reelin gene expression levels. J Neural Transm. 2006;113:1373–82.

    Article  PubMed  CAS  Google Scholar 

  241. Eskenazi B, Huen K, Marks A, Harley KG, Bradman A, Barr DB, et al. PON1 and neurodevelopment in children from the CHAMACOS study exposed to organophosphate pesticides in utero. Environ Health Perspect. 2010;118:1775–81.

    Article  PubMed  CAS  Google Scholar 

  242. Mullen B, Khialeeva E, Carpenter EM. Dab1-lacZ reporter reveals CNS lamination defects in a mouse model for autism. Program no. 147.12, 2010 Neuroscience Meeting Planner. Society for Neuroscience, San Diego CA. online.

  243. Krey J, Dolmetsch R. Molecular mechanisms of autism: a possible role for Ca2+ signaling. Curr Opin Neurobiol. 2007;17:112–9.

    Article  PubMed  CAS  Google Scholar 

  244. Empson RM, Garside ML, Knöpfel T. Plasma membrane Ca2+ ATPase 2 contributes to short-term synapse plasticity at the parallel fiber to Purkinje neuron synapse. J Neurosci. 2007;27:3753–8.

    Article  PubMed  CAS  Google Scholar 

  245. Burette AC, Strehler EE, Weinberg RJ. “Fast” plasma membrane calcium pump PMCA2a concentrates in GABAergic terminals in the adult rat brain. J Comp Neurol. 2009;512:500–13.

    Article  PubMed  Google Scholar 

  246. Garside ML, Turner PR, Austen B, Strehler EE, Beesley PW, Empson RM. Molecular interactions of the plasma membrane calcium ATPase 2 at pre- and post-synaptic sites in rat cerebellum. Neuroscience. 2009;162:383–95.

    Article  PubMed  CAS  Google Scholar 

  247. Carayol J, Sacco R, Tores F, Rousseau F, Lewin P, Hager J, et al. Converging evidence for an association of ATP2B2 allelic variants with autism in males. Biol Psychiatry. 2011;70(9):880–7.

    Article  PubMed  CAS  Google Scholar 

  248. Pessah IN, Cherednichenko G, Lein PJ. Minding the calcium store: ryanodine receptor activation as a convergent mechanism of PCB toxicity. Pharmacol Ther. 2010;125:260–85.

    Article  PubMed  CAS  Google Scholar 

  249. Palmieri L, Persico AM. Mitochondrial dysfunction in autism spectrum disorders: cause or effect? Biochim Biophys Acta. 2010;1797:1130–7.

    Article  PubMed  CAS  Google Scholar 

  250. Elsen GE, Choi LY, Prince VE, Ho RK. The autism susceptibility gene met regulates zebrafish cerebellar development and facial motor neuron migration. Dev Biol. 2009;335:78–92.

    Article  PubMed  CAS  Google Scholar 

  251. Campbell DB, D’Oronzio R, Garbett K, Ebert PJ, Mirnics K, Levitt P, et al. Disruption of cerebral cortex MET signaling in autism spectrum disorder. Ann Neurol. 2007;62:243–50.

    Article  PubMed  Google Scholar 

  252. Campbell DB, Sutcliffe JS, Ebert PJ, Militerni R, Bravaccio C, Trillo S, et al. A genetic variant that disrupts MET transcription is associated with autism. Proc Natl Acad Sci USA. 2006;103:16834–9.

    Article  PubMed  CAS  Google Scholar 

  253. Sheng L, Ding X, Ferguson M, McCallister M, Rhoades R, Maguire M, et al. Prenatal polycyclic aromatic hydrocarbon exposure leads to behavioral deficits and downregulation of receptor tyrosine kinase, MET. Toxicol Sci. 2010;118:625–34.

    Article  PubMed  CAS  Google Scholar 

  254. Campbell DB, Li C, Sutcliffe JS, Persico AM, Levitt P. Genetic evidence implicating multiple genes in the MET receptor tyrosine kinase pathway in autism spectrum disorder. Autism Res. 2008;1:159–68.

    Article  PubMed  Google Scholar 

  255. Carlson GC. Glutamate receptor dysfunction and drug targets across models of autism spectrum disorders. Pharmacol Biochem Behav. 2012;100(4):850–4.

    Article  PubMed  CAS  Google Scholar 

  256. Steinlin M. Cerebellar disorders in childhood: cognitive problems. Cerebellum. 2008;7:607–10.

    Article  PubMed  Google Scholar 

  257. Rojas DC, Peterson E, Winterrowd E, Reite ML, Rogers SJ, Tregellas JR. Regional gray matter volumetric changes in autism associated with social and repetitive behavior symptoms. BMC Psychiatry. 2006;6:56.

    Article  PubMed  Google Scholar 

  258. Schmahmann JD, Weilburg JB, Sherman JC. The neuropsychiatry of the cerebellum—insights from the clinic. Cerebellum. 2007;6:254–67.

    Article  PubMed  Google Scholar 

  259. Anderson CM, Polcari A, Lowen SB, Renshaw PF, Teicher MH. Effects of methylphenidate on functional magnetic resonance relaxometry of the cerebellar vermis in boys with ADHD. Am J Psychiatry. 2002;159:1322–8.

    Article  PubMed  Google Scholar 

  260. Takahashi T, Kobayashi T, Ozaki M, Takamatsu Y, Ogai Y, Ohta M, et al. G protein-activated inwardly rectifying K+ channel inhibition and rescue of weaver mouse motor functions by antidepressants. Neurosci Res. 2006;54:104–11.

    Article  PubMed  CAS  Google Scholar 

  261. Blatt GJ. GABAergic cerebellar system in autism: a neuropathological and developmental perspective. Int Rev Neurobiol. 2005;71:167–78.

    Article  PubMed  CAS  Google Scholar 

  262. Johannessen Landmark C. Antiepileptic drugs in non-epilepsy disorders: relations between mechanisms of action and clinical efficacy. CNS Drugs. 2008;22:27–47.

    Article  PubMed  Google Scholar 

  263. Fink M, Taylor MA, Ghaziuddin N. Catatonia in autistic spectrum disorders: a medical treatment algorithm. Int Rev Neurobiol. 2006;72:233–44.

    Article  PubMed  Google Scholar 

  264. Wang P, Erickson CA, Ginsberg G, Rathmell B, Cerubini M, Zarevics P, et al. Effects of STX209 (arbaclofen) on social and communicative function in ASD: results of an 8 week open label trial. International Meeting for Autism Research. 2011 May. San Diego, CA.

  265. Lory P, Mezghrani A. Calcium channelopathies in inherited neurological disorders: relevance to drug screening for acquired channel disorders. IDrugs. 2010;13:467–71.

    PubMed  CAS  Google Scholar 

  266. Placantonakis DG, Schwarz C, Welsh JP. Serotonin suppresses subthreshold and suprathreshold oscillatory activity of rat inferior olive neurons in vitro. J Physiol (Lond). 2000;524:833–51.

    Article  CAS  Google Scholar 

  267. Placantonakis DG, Welsh JP. Two distinct oscillatory states determined by the NMDA receptor in rat inferior olive. J Physiol (Lond). 2001;534:123–40.

    Article  CAS  Google Scholar 

  268. Welsh JP, Han VZ. The NMDA receptor potentiates electrotonic coupling between inferior olive neurons. Society for Neuroscience Abstracts. 2010; 525–5.

  269. Park YG, Park HY, Lee CJ, Choi S, Jo S, Choi H, et al. Ca(V)3.1 is a tremor rhythm pacemaker in the inferior olive. Proc Nat Acad Sci (USA). 2010;107:10731–6.

    Article  CAS  Google Scholar 

  270. Cheung C, Chua S, Cheung V, Khong P, Tai K, Wong T, et al. White matter fractional anisotrophy differences and correlates of diagnostic symptoms in autism. J Child Psychol Psychiatry. 2009;50:1102–12.

    Article  PubMed  CAS  Google Scholar 

  271. Catani M, Jones DK, Daly E, Embiricos N, Deeley Q, Pugliese L, et al. Altered cerebellar feedback projections in Asperger syndrome. NeuroImage. 2008;41:1184–91.

    Article  PubMed  Google Scholar 

  272. Kates WR, Burnette CP, Eliez S, Strunge LA, Kaplan D, Landa R, et al. Neuroanatomic variation in monozygotic twin pairs discordant for the narrow phenotype for autism. Am J Psychiatry. 2004;161:539–46.

    Article  PubMed  Google Scholar 

  273. Amaral DG, Schumann CM, Nordahl CW. Neuroanatomy of autism. Trends Neurosci. 2008;31:137–45.

    Article  PubMed  CAS  Google Scholar 

  274. Bellebaum C, Daum I. Cerebellar involvement in executive control. Cerebellum. 2007;6:184–92.

    Article  PubMed  Google Scholar 

  275. Pennington BF, Ozonoff S. Executive functions and developmental psychopathology. J Child Psychol Psychiatry. 1996;37:51–87.

    Article  PubMed  CAS  Google Scholar 

  276. Lopez BR, Lincoln AJ, Ozonoff S, Lai Z. Examining the relationship between executive functions and restricted, repetitive symptoms of autistic disorder. J Autism Dev Disord. 2005;35:445–60.

    Article  PubMed  Google Scholar 

  277. Giza J, Urbanski MJ, Prestori F, Bandyopadhyay B, Yam A, Friedrich V, et al. Behavioral and cerebellar transmission deficits in mice lacking the autism-linked gene islet brain-2. J Neurosci. 2010;30:14805–16.

    Article  PubMed  CAS  Google Scholar 

  278. Swanson DJ, Goldowitz D. Experimental Sey mouse chimeras reveal the developmental deficiencies of Pax6-null granule cells in the postnatal cerebellum. Dev Biol. 2011;351(1):1–12.

    Article  PubMed  CAS  Google Scholar 

  279. Umeda T, Takashima N, Nakagawa R, Maekawa M, Ikegami S, Yoshikawa T, et al. Evaluation of Pax6 mutant rat as a model for a autism. PLoS One. 2010;5(12):e15500.

    Article  PubMed  CAS  Google Scholar 

  280. Kuemerle B, Gulden F, Cherosky N, Williams E, Herrup K. The mouse Engrailed genes: a window into autism. Behav Brain Res. 2007;176(1):121–32.

    Article  PubMed  CAS  Google Scholar 

  281. Rasalam AD, Hailey H, Williams JH, Moore SJ, Turnpenny PD, Lloyd DJ, et al. Characteristics of fetal anticonvulsant syndrome associated autistic disorder. Dev Med Child Neurol. 2005;47(8):551–5.

    Article  PubMed  CAS  Google Scholar 

  282. Ingram JL, Stodgell CJ, Hyman SL, Figlewicz DA, Weitkamp LR, Rodier PM. Discovery of allelic variants of HOXA1 and HOXB1: genetic susceptibility to autism spectrum disorders. Teratology. 2000;62(6):393–405.

    Article  PubMed  CAS  Google Scholar 

  283. Zuo J, De Jager PL, Takahashi KA, Jiang W, Linden DJ, Heintz N. Neurodegeneration in Lurcher mice caused by mutation in delta2 glutamate receptor gene. Nature. 1997;388:769–73.

    Article  PubMed  CAS  Google Scholar 

  284. Dickson PE, Rogers TD, Del Mar N, Martin LA, Heck D, Blaha CD, et al. Behavioral flexibility in a mouse model of developmental cerebellar Purkinje cell loss. Neurobiol Learn Mem. 2010;94:220–8.

    Article  PubMed  Google Scholar 

  285. Martin LA, Escher T, Goldowitz D, Mittleman G. A relationship between cerebellar Purkinje cells and spatial working memory demonstrated in a lurcher/chimera mouse model system. Genes Brain Behav. 2004;3:158–66.

    Article  PubMed  CAS  Google Scholar 

  286. Martin LA, Goldowitz D, Mittleman G. Sustained attention in the mouse: a study of the relationship with the cerebellum. Behav Neurosci. 2006;120(2):477–81.

    Article  PubMed  Google Scholar 

  287. Martin LA, Goldowitz D, Mittleman G. Repetitive behavior and increased activity in mice with Purkinje cell loss: a model for understanding the role of cerebellar pathology in autism. Eur J Neurosci. 2010;31:544–55.

    Article  PubMed  Google Scholar 

  288. Courchesne E, Mouton PR, Calhoun ME, Semendeferi K, Ahrens-Barbeau C, Hallet MJ, et al. Neuron number and size in prefrontal cortex of children with autism. JAMA. 2011;306(18):2001–32.

    Article  PubMed  CAS  Google Scholar 

  289. Fatemi SH, Folsom TD. The role of fragile X mental retardation protein in major mental disorders. Neuropharmacology. 2011;60:1221–6.

    Article  PubMed  CAS  Google Scholar 

  290. Martin LA, Goldowitz D, Mittleman G. Sustained attention in the mouse: a study of the relationship with the cerebellum. Behav Neurosci. 2006;120(2):477–81.

    Article  PubMed  Google Scholar 

  291. Ozonoff S, Williams BJ, Gale S, Miller JN. Autism and autistic behavior in Joubert syndrome. J Child Neurol. 1999;14(10):636–41.

    Article  PubMed  CAS  Google Scholar 

  292. Lancaster MA, Gopal DJ, Kim J, Saleem SN, Silhavy JL, Louie CM, et al. Defective Wnt-dependent cerebellar midline fusion in a mouse model of Joubert syndrome. Nat Med. 2011;17(6):726–31.

    Article  PubMed  CAS  Google Scholar 

  293. Garcia CA, McGarry PA, Voirol M, Duncan C. Neurological involvement in the Smith-Lemli-Opitz syndrome: clinical and neuropathological findings. Dev Med Child Neurol. 1973;15(1):48–55.

    Article  PubMed  CAS  Google Scholar 

  294. Ellegood J, Pacey LK, Hampson DR, Lerch JP, Henkelman RM. Anatomical phenotyping in a mouse model of fragile X syndrome with magnetic resonance imaging. NeuroImage. 2010;53(3):1023–9.

    Article  PubMed  Google Scholar 

  295. Bauman ML, Kemper TL, Arin DM. Microscopic observations of the brain in Rett syndrome. Neuropediatrics. 1995;26(2):105–8.

    Article  PubMed  CAS  Google Scholar 

  296. Belichenko NP, Belichenko PV, Li HH, Mobley WC, Francke U. Comparative study of brain morphology in Mecp2 mutant mouse models of Rett syndrome. J Comp Neurol. 2008;508(1):184–95.

    Article  PubMed  Google Scholar 

  297. Alkan A, Sigirci A, Kutlu R, Ozcan H, Erdem G, Aslan M, et al. Neurofibromatosis type 1: diffusion weighted imaging findings of brain. Eur J Radiol. 2005;56(2):229–34.

    Article  PubMed  Google Scholar 

  298. van der Vaart T, van Woerden GM, Elgersma Y, de Zeeuw CI, Schonewille M. Motor deficits in neurofibromatosis type 1 mice: the role of the cerebellum. Genes Brain Behav. 2011;10(4):404–9.

    Article  PubMed  Google Scholar 

  299. Padberg GW, Schot JD, Vielvoye GJ, Bots GT, de Beer FC. Lhermitte-Duclos disease and Cowden disease: a single phakomatosis. Ann Neurol. 1991;29(5):517–23.

    Article  PubMed  CAS  Google Scholar 

  300. Kwon CH, Zhu X, Zhang J, Knoop LL, Tharp R, Smeyne RJ, et al. Pten regulates neuronal soma size: a mouse model of Lhermitte-Duclos disease. Nat Genet. 2001;29(4):404–11.

    Article  PubMed  CAS  Google Scholar 

  301. Reith RM, Way S, McKenna 3rd J, Haines K, Gambello MJ. Loss of the tuberous sclerosis complex protein tuberin causes Purkinje cell degeneration. Neurobiol Dis. 2011;43(1):113–22.

    Article  PubMed  CAS  Google Scholar 

  302. Asahina N, Shiga T, Egawa K, Shiraishi H, Kohsaka S, Saitoh S. [(11)C]flumazenil positron emission tomography analyses of brain gamma-aminobutyric acid type A receptors in Angelman syndrome. J Pediatr. 2008;152(4):546–9. 9 e1-3.

    Article  PubMed  CAS  Google Scholar 

  303. Dindot SV, Antalffy BA, Bhattacharjee MB, Beaudet AL. The Angelman syndrome ubiquitin ligase localizes to the synapse and nucleus, and maternal deficiency results in abnormal dendritic spine morphology. Hum Mol Genet. 2008;17(1):111–8.

    Article  PubMed  CAS  Google Scholar 

  304. Uemura T, Lee SJ, Yasumura M, Takeuchi T, Yoshida T, Ra M, et al. Trans-synaptic interaction of GluRdelta2 and Neurexin through Cbln1 mediates synapse formation in the cerebellum. Cell. 2010;141(6):1068–79.

    Article  PubMed  CAS  Google Scholar 

  305. Tan GC, Doke TF, Ashburner J, Wood NW, Frackowiak RS. Normal variation in fronto-occipital circuitry and cerebellar structure with an autism-associated polymorphism of CNTNAP2. NeuroImage. 2010;53(3):1030–42.

    Article  PubMed  CAS  Google Scholar 

  306. Crepel F. Developmental changes in retrograde messengers involved in depolarization-induced suppression of excitation at parallel fiber-Purkinje cell synapses in rodents. J Neurophysiol. 2007;97(1):824–36.

    Article  PubMed  CAS  Google Scholar 

  307. Hong SE, Shugart YY, Huang DT, Shahwan SA, Grant PE, Hourihane JO, et al. Autosomal recessive lissencephaly with cerebellar hypoplasia is associated with human RELN mutations. Nat Genet. 2000;26(1):93–6.

    Article  PubMed  CAS  Google Scholar 

  308. D’Arcangelo G, Miao GG, Chen SC, Soares HD, Morgan JI, Curran T. A protein related to extracellular matrix proteins deleted in the mouse mutant reeler. Nature. 1995;374(6524):719–23.

    Article  PubMed  Google Scholar 

  309. Sakurai T, Ramoz N, Barreto M, Gazdoiu M, Takahashi N, Gertner M, et al. Slc25a12 disruption alters myelination and neurofilaments: a model for a hypomyelination syndrome and childhood neurodevelopmental disorders. Biol Psychiatry. 2010;67(9):887–94.

    Article  PubMed  CAS  Google Scholar 

  310. Manni E, Petrosini L. A century of cerebellar somatotopy: a debated representation. Nat Rev Neurosci. 2004;5(3):241–9.

    Article  PubMed  CAS  Google Scholar 

  311. Fatemi SH, Halt AR, Realmuto G, Earle J, Kist DA, Thuras P, et al. Purkinje cell size is reduced in the cerebellum of patients with autism. Cell Mol Neurobiol. 2002;22(2):171–5.

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

(1) Dr. S. Hossein Fatemi appreciates the excellent technical assistance by Rachel Elizabeth Kneeland in editing of this consensus paper, and the critical review of the manuscript by Mr. Timothy D. Folsom. Research support for Dr. Fatemi’s work is from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (5R01HD052074-05 and 3R01HD05207403-S1 supplemental grant), as well as the Alfred and Ingrid Lenz Harrison Autism Initiative; (2) Research support for work by Drs. Kimberly A. Aldinger and Kathleen J. Millen is from the Autism Speaks Foundation; (3) Research support for work by Dr. Paul Ashwood is from Autism Speaks Foundation, the Jane Botsford Johnson Foundation, National Alliance for Research on Schizophrenia and Depression, and National Institute of Neurological Disorders and Stroke R21HD065269, and the Peter Emch Foundation is gratefully acknowledged; (4) Research support for work by Drs. Margaret L. Bauman and Thomas L. Kemper is from the Nancy Lurie Marks Family Foundation, by NINDS (NS38975-05) and by NAAR/Autism Speaks. We would also like to acknowledge and thank the many families whose generous donation of postmortem brain tissue has made this research possible; (5) Research support for work by Drs. Charles D. Blaha, Price E. Dickson, Dan Goldowitz, Loren A. Martin, and Guy Mittleman is from Cure Autism Now, Autism Speaks, and R01 NS063009 from NIH/NINDS; (6) Research support for work by Dr. Gene Blatt is from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (5R01HD039459-06) and The Hussman Foundation; (7) Research support for work by Drs. Abha Chauhan and Ved Chauhan is from the Department of Defense Autism Spectrum Disorders Research Program AS073224P2, the Autism Research Institute, the Autism Collaboration (autism.org), and the NYS Office for People with Developmental Disabilities; (8) Drs. Stephen R. Dager, Annette M. Estes, and John P. Welsh would like to thank Elizabeth Kelly for assistance in preparing their manuscript. Research support for their work is from Autism Centers of Excellence (NICHD P50-HD055782), Collaborative Programs of Excellence in Autism (NICHD #HD35465 NICHD, RO1-HD055741), ACE Network (NICHD RO1 supplement HD05571), American Recovery and Reinvestment Act (NICHD R01-HD065283), and National Institute for Neurological Disorders and Stroke (NINDS R01-NS31224-18). Support from Autism Speaks and the Simons Foundation is also gratefully acknowledged; (9) Research support for Dr. Detlef H. Heck is from NIH grants RO1NS060887 and R01NS063009. The content of this publication is solely the responsibility of the author and does not necessarily represent the official views of the NIH; (10) Research support for Drs. Bryan H. King, Sara J. Webb, and John P. Welsh is from the Eunice Kennedy Shriver National Institute of Child Health & Human Development (P50 HD055782; King/Webb) and the National Institute for Neurological Disorders and Stroke (R01 NS31224-18; Welsh). We want to thank the families of and individuals with autism who have participated in research; (11) Research support for work by Drs. Matthew W. Mosconi and John A. Sweeney is from the Autism Center of Excellence Award Number P50HD055751 from the Eunice Kennedy Shriver NICHD, NIMH Grant 1K23MH092696, and Autism Speaks Grant 4853. Dr. John Sweeney consults with Pfizer and Takeda and has received a grant from the Janssen Foundation. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding institutes; (12) Research support for work by Dr. Antonio M. Persico is from the Italian Ministry of University, Research and Technology (PRIN 2006058195 and 2008BACT54), the Italian Ministry of Health (RFPS-2007-5-640174), Autism Speaks (Princeton, NJ), the Autism Research Institute (San Diego, CA), and the Fondazione Gaetano e Mafalda Luce (Milan, Italy).

Conflicts of interest

The authors declare that they have no conflicts of interest.

Author information

Authors and Affiliations

  1. University of Minnesota Medical School, 420 Delaware St. SE, MMC 392, Minneapolis, MN, 55455, USA

    S. Hossein Fatemi

  2. Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, USA

    Kimberly A. Aldinger

  3. Department of Medical Microbiology and Immunology, The Medical Investigation of Neurodevelopmental Disorders (M.I.N.D.) Institute, University of California, Davis, USA

    Paul Ashwood

  4. Harvard Medical School, Boston, USA

    Margaret L. Bauman

  5. Department of Pediatrics and Neurology, Massachusetts General Hospital, Boston, USA

    Margaret L. Bauman

  6. Department of Psychology, University of Memphis, Tennessee, USA

    Charles D. Blaha, Price E. Dickson & Guy Mittleman

  7. Department of Anatomy and Neurobiology, Boston University School of Medicine, Boston, MA, USA

    Gene J. Blatt

  8. NYS Institute for Basic Research in Developmental Disabilities, Staten Island, NY, USA

    Abha Chauhan & Ved Chauhan

  9. Departments of Radiology and Bioengineering, University of Washington, Seattle, USA

    Stephen R. Dager

  10. Autism Center, University of Washington, Seattle, USA

    Stephen R. Dager & Annette M. Estes

  11. Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics, University of British Columbia, Vancouver, Canada

    Dan Goldowitz

  12. Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, USA

    Detlef H. Heck

  13. Department of Anatomy and Neurobiology, Boston University School of Medicine, Boston, USA

    Thomas L. Kemper

  14. Department of Psychiatry and Behavioral Sciences, University of Washington Seattle Children’s Autism Center, Seattle, USA

    Bryan H. King & Sara J. Webb

  15. Department of Psychology, Azusa Pacific University, Azusa, CA, USA

    Loren A. Martin

  16. Seattle Children’s Research Institute and Department of Pediatrics, University of Washington, Seattle, USA

    Kathleen J. Millen

  17. Departments of Psychiatry and Pediatrics, University of Texas Southwestern Medical Center, Dallas, USA

    Matthew W. Mosconi & John A. Sweeney

  18. Child Neuropsychiatry Unit, Laboratory of Molecular Psychiatry and Neurogenetics, University Campus Bio-Medico, and Department of Experimental Neurosciences, I.R.C.C.S. “Fondazione Santa Lucia”, Rome, Italy

    Antonio M. Persico

  19. Center for Integrative Brain Research, Seattle Children’s Research Institute Department of Pediatrics, University of Washington, Seattle, USA

    John P. Welsh

Authors
  1. S. Hossein Fatemi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kimberly A. Aldinger
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Paul Ashwood
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Margaret L. Bauman
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Charles D. Blaha
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Gene J. Blatt
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Abha Chauhan
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ved Chauhan
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Stephen R. Dager
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Price E. Dickson
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Annette M. Estes
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Dan Goldowitz
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Detlef H. Heck
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Thomas L. Kemper
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Bryan H. King
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Loren A. Martin
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Kathleen J. Millen
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Guy Mittleman
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Matthew W. Mosconi
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Antonio M. Persico
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. John A. Sweeney
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Sara J. Webb
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. John P. Welsh
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to S. Hossein Fatemi.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fatemi, S.H., Aldinger, K.A., Ashwood, P. et al. Consensus Paper: Pathological Role of the Cerebellum in Autism. Cerebellum 11, 777–807 (2012). https://doi.org/10.1007/s12311-012-0355-9

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12311-012-0355-9

Keywords

Search

Navigation