Autism spectrum disorders and neuropathology of the cerebellum

Frontiers in Neuroscience

Volumn 9, Issue NOV, 2015, Pages

  Hampson, David R ^a   Blatt, Gene J ^b  

^a UNIVERSITY OF TORONTO   (Canada)

^b Hussman Institute for Autism   (United States)

Author keywords

Apraxia of speech; Cerebellar cognitive affective syndrome; Cerebellar vermis; Deep cerebellar nuclei; Fragile X syndrome; Inferior olivary complex; Purkinje cell; Tuberous sclerosis

Indexed keywords

ANTIGEN; AUTOANTIBODY; CEREBELLARANTIGEN; UNCLASSIFIED DRUG;

AUTISM; AUTOPSY; CEREBELLUM; CEREBELLUM DISEASE; CLINICAL FEATURE; DIAGNOSTIC TEST; DISEASE ASSOCIATION; DISEASE CLASSIFICATION; FRAGILE X SYNDROME; GENETIC ASSOCIATION; HUMAN; IDIOPATHIC DISEASE; KNOCKOUT MOUSE; LANGUAGE ABILITY; MENTAL CAPACITY; MOTOR ACTIVITY; MOTOR COORDINATION; MOUSE MODEL; NEUROANATOMY; NEUROIMAGING; NEUROPATHOLOGY; NONHUMAN; PATHOGENESIS; RETT SYNDROME; REVIEW; TUBEROUS SCLEROSIS;

EID: 84949546222     PISSN: 16624548     EISSN: 1662453X     Source Type: Journal    
DOI: 10.3389/fnins.2015.00420     Document Type: Review

References (159)

1. Altman, J., and Bayer, S. A. (1978). Prenatal development of the cerebellar system in the rat. I. Cytogenesis and histogenesis of the deep nuclei and the cortex of the cerebellum. J. Comp. Neurol. 179, 23-48. doi: 10.1002/cne.901790104.
2. Armstrong, D. D. (1992). The neuropathology of the Rett syndrome. Brain Dev. 14(Suppl.) S89-S98.
3. Armstrong, D. D. (2005). Neuropathology of Rett syndrome. J. Child Neurol. 20, 747-753. doi: 10.1177/08830738050200082401.
4. Atladóttir, H. O., Thorsen, P., Østergaard, L., Schendel, D. E., Lemcke, S., Abdallah, M., et al. (2010a). Maternal infection requiring hospitalization during pregnancy and autism spectrum disorders. J. Autism Dev. Disord. 40, 1423-1430. doi: 10.1007/s10803-010-1006-y.
5. Atladóttir, H. O., Thorsen, P., Schendel, D. E., Østergaard, L., Lemcke, S., and Parner, E. T. (2010b). Association of hospitalization for infection in childhood with diagnosis of autism spectrum disorders: a Danish cohort study. Arch. Pediatr. Adolesc. Med. 164, 470-477. doi: 10.1001/archpediatrics.2010.9.
6. Auerbach, B. D., Osterweil, E. K., and Bear, M. F. (2011). Mutations causing syndromic autism define an axis of synaptic pathophysiology. Nature 480, 63-68. doi: 10.1038/nature10658.
7. Bagni, C., Tassone, F., Neri, G., and Hagerman, R. (2012). Fragile X syndrome: causes, diagnosis, mechanisms, and therapeutics. J. Clin. Invest. 122, 4314-4322. doi: 10.1172/JCI63141.
8. Bailey, A., Luthert, P., Dean, A., Harding, B., Janota, I., Montgomery, M., et al. (1998). A clinicopathological study of autism. Brain 121 (Pt 5), 889-905.
9. Balsters, J. H., Cussans, E., Diedrichsen, J., Phillips, K. A., Preuss, T. M., Rilling, J. K., et al. (2010). Evolution of the cerebellar cortex: the selective expansion of prefrontal-projecting cerebellar lobules. Neuroimage 49, 2045-2052. doi: 10.1016/j.neuroimage.2009.10.045.
10. Barton, R. A., and Venditti, C. (2014). Rapid evolution of the cerebellum in humans and other great apes. Curr. Biol. 24, 2440-2444. doi: 10.1016/j.cub.2014.08.056.
11. Baum, K. T., Shear, P. K., Howe, S. R., and Bishop, S. L. (2014). A comparison of WISC-IV and SB-5 intelligence scores in adolescents with autism spectrum disorder. Autism 19, 736-745. doi: 10.1177/1362361314554920.
12. Bauman, M., and Kemper, T. L. (1985). Histoanatomic observations of the brain in early infantile autism. Neurology 35, 866-874.
13. Bauman, M. L., Kemper, T. L., and Arin, D. M. (1995). Pervasive neuroanatomic abnormalities of the brain in three cases of Rett's syndrome. Neurology 45, 1581-1586.
14. Berry-Kravis, E. (2002). Epilepsy in fragile X syndrome. Dev. Med. Child Neurol. 44, 724-728. doi: 10.1111/j.1469-8749.2002.tb00277.x.
15. Betancur, C. (2011). Etiological heterogeneity in autism spectrum disorders: more than 100 genetic and genomic disorders and still counting. Brain Res. 1380, 42-77. doi: 10.1016/j.brainres.2010.11.078.
16. Blatt, G. J. (2012). The neuropathology of autism. Sci. (Cairo). 2012:703675. doi: 10.6064/2012/703675.
17. Blatt, G. J., and Eisenman, L. M. (1988). Topographic and zonal organization of the olivocerebellar projection in the reeler mutant mouse. J. Comp. Neurol. 267, 603-615. doi: 10.1002/cne.902670412.
18. Blatt, G. J., and Eisenman, L. M. (1989). Regional and topographic organization of the olivocerebellar projection in homozygous staggerer (sg/sg) mutant mice: an anterograde and retrograde tracing study. Neuroscience 30, 703-715.
19. Blatt, G. J., and Eisenman, L. M. (1993). The olivocerebellar projection in normal (+/+), heterozygous weaver (wv/+), and homozygous weaver (wv/wv) mutant mice: comparison of terminal pattern and topographic organization. Exp. Brain Res. 95, 187-201.
20. Blatt, G. J., Fitzgerald, C. M., Guptill, J. T., Booker, A. B., Kemper, T. L., and Bauman, M. L. (2001). Density and distribution of hippocampal neurotransmitter receptors in autism: an autoradiographic study. J. Autism Dev. Disord. 31, 537-543. doi: 10.1023/A:1013238809666.
21. Bolduc, M. E., du Plessis, A. J., Sullivan, N., Guizard, N., Zhang, X., Robertson, R. L., et al. (2012). Regional cerebellar volumes predict functional outcome in children with cerebellar malformations. Cerebellum 11, 531-542. doi: 10.1007/s12311-011-0312-z.
22. Bolduc, M. E., Du Plessis, A. J., Sullivan, N., Khwaja, O. S., Zhang, X., Barnes, K., et al. (2011). Spectrum of neurodevelopmental disabilities in children with cerebellar malformations. Dev. Med. Child Neurol. 53, 409-416. doi: 10.1111/j.1469-8749.2011.03929.x.
23. Brodal, A. (1969). Neurological Anatomy in Relation to Clinical Medicine. New York, NY: Oxford University Press.
24. Broussard, D. M. (2014). The Cerebellum: Learning Movement, Language, and Social Skills. Chichester: John Wiley & Sons, Inc.
25. Brown, A. S. (2012). Epidemiologic studies of exposure to prenatal infection and risk of schizophrenia and autism. Dev. Neurobiol. 72, 1272-1276. doi: 10.1002/dneu.22024.
26. Budimirovic, D. B., and Kaufmann, W. E. (2011). What can we learn about autism from studying fragile X syndrome? Dev. Neurosci. 33, 379-394. doi: 10.1159/000330213.
27. Casanova, M. F., Buxhoeveden, D., Switala, A., and Roy, E. (2003). Rett syndrome as a minicolumnopathy. Clin. Neuropathol. 22, 163-168.
28. Chan-Palay, V. (1977). Cerebellar Dentate Nucleus. Berlin; New York, NY: Springer-Verlag.
29. Charman, T. (2011). The highs and lows of counting autism. Am. J. Psychiatry 168, 873-875. doi: 10.1176/appi.ajp.2011.11060897.
30. Chen, C. H., Huang, C. C., Cheng, M. C., Chiu, Y. N., Tsai, W. C., Wu, Y. Y., et al. (2014). Genetic analysis of GABRB3 as a candidate gene of autism spectrum disorders. Mol. Autism 5:36. doi: 10.1186/2040-2392-5-36.
31. Cheng, Y., Sudarov, A., Szulc, K. U., Sgaier, S. K., Stephen, D., Turnbull, D. H., et al. (2010). The Engrailed homeobox genes determine the different foliation patterns in the vermis and hemispheres of the mammalian cerebellum. Development 137, 519-529. doi: 10.1242/dev.027045.
32. Cheung, C., Chua, S. E., Cheung, V., Khong, P. L., Tai, K. S., Wong, T. K., et al. (2009). White matter fractional anisotrophy differences and correlates of diagnostic symptoms in autism. J. Child Psychol. Psychiatry 50, 1102-1112. doi: 10.1111/j.1469-7610.2009.02086.x.
33. Choi, J., Ababon, M. R., Soliman, M., Lin, Y., Brzustowicz, L. M., Matteson, P. G., et al. (2014). Autism associated gene, engrailed2, and flanking gene levels are altered in post-mortem cerebellum. PLoS ONE 9:e87208. doi: 10.1371/journal.pone.0087208.
34. Chu-Shore, C. J., Major, P., Montenegro, M., and Thiele, E. (2009). Cyst-like tubers are associated with TSC2 and epilepsy in tuberous sclerosis complex. Neurology 72, 1165-1169. doi: 10.1212/01.wnl.0000345365.92821.86.
35. Courchesne, E., and Pierce, K. (2005). Brain overgrowth in autism during a critical time in development: implications for frontal pyramidal neuron and interneuron development and connectivity. Int. J. Dev. Neurosci. 23, 153-170. doi: 10.1016/j.ijdevneu.2005.01.003.
36. Courchesne, E., Saitoh, O., Yeung-Courchesne, R., Press, G. A., Lincoln, A. J., Haas, R. H., et al. (1994). Abnormality of cerebellar vermian lobules VI and VII in patients with infantile autism: identification of hypoplastic and hyperplastic subgroups with MR imaging. Am. J. Roentgenol. 162, 123-130. doi: 10.2214/ajr.162.1.8273650.
37. Courchesne, E., Yeung-Courchesne, R., Press, G. A., Hesselink, J. R., and Jernigan, T. L. (1988). Hypoplasia of cerebellar vermal lobules VI and VII in autism. N. Engl. J. Med. 318, 1349-1354. doi: 10.1056/NEJM198805263182102.
38. Crepel, F., and Mariani, J. (1976). Multiple innervation of Purkinje cells by climbing fibers in the cerebellum of the Weaver Mutant Mouse. J. Neurobiol. 7, 579-582. doi: 10.1002/neu.480070610.
39. DeLorey, T. M., Sahbaie, P., Hashemi, E., Homanics, G. E., and Clark, J. D. (2008). 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. 187, 207-220. doi: 10.1016/j.bbr.2007.09.009.
40. Dickson, P. E., Rogers, T. D., Del Mar, N., Martin, L. A., Heck, D., Blaha, C. D., et al. (2010). Behavioral flexibility in a mouse model of developmental cerebellar Purkinje cell loss. Neurobiol. Learn. Mem. 94, 220-228. doi: 10.1016/j.nlm.2010.05.010.
41. Diño, M. R., Perachio, A. A., and Mugnaini, E. (2001). Cerebellar unipolar brush cells are targets of primary vestibular afferents: an experimental study in the gerbil. Exp. Brain Res. 140, 162-170. doi: 10.1007/s002210100790.
42. Ebrahimi-Fakhari, D., and Sahin, M. (2015). Autism and the synapse: emerging mechanisms and mechanism-based therapies. Curr. Opin. Neurol. 28, 91-102. doi: 10.1097/WCO.0000000000000186.
43. Eccles, J. C. (1967). Circuits in the cerebellar control of movement. Proc. Natl. Acad. Sci. U.S.A. 58, 336-343.
44. Eccles, J. C., Ito, M., and Szentágothai, J. (1967). The Cerebellum as a Neuronal Machine. Berlin; Heidelberg: Springer.
45. Ecker, C., Suckling, J., Deoni, S. C., Lombardo, M. V., Bullmore, E. T., Baron-Cohen, S., et al. (2012). Brain anatomy and its relationship to behavior in adults with autism spectrum disorder: a multicenter magnetic resonance imaging study. Arch. Gen. Psychiatry 69, 195-209. doi: 10.1001/archgenpsychiatry.2011.1251.
46. Ellegood, J., Anagnostou, E., Babineau, B. A., Crawley, J. N., Lin, L., Genestine, M., et al. (2015). Clustering autism: using neuroanatomical differences in 26 mouse models to gain insight into the heterogeneity. Mol. Psychiatry 20, 118-125. doi: 10.1038/mp.2014.98.
47. Ellegood, J., Pacey, L. K., Hampson, D. R., Lerch, J. P., and Henkelman, R. M. (2010). Anatomical phenotyping in a mouse model of fragile X syndrome with magnetic resonance imaging. Neuroimage 53, 1023-1029. doi: 10.1016/j.neuroimage.2010.03.038.
48. Eluvathingal, T. J., Behen, M. E., Chugani, H. T., Janisse, J., Bernardi, B., Chakraborty, P., et al. (2006). Cerebellar lesions in tuberous sclerosis complex: neurobehavioral and neuroimaging correlates. J. Child Neurol. 21, 846-851. doi: 10.1177/08830738060210100301.
49. Englund, C., Kowalczyk, T., Daza, R. A., Dagan, A., Lau, C., Rose, M. F., et al. (2006). Unipolar brush cells of the cerebellum are produced in the rhombic lip and migrate through developing white matter. J. Neurosci. 26, 9184-9195. doi: 10.1523/JNEUROSCI.1610-06.2006.
50. Ertan, G., Arulrajah, S., Tekes, A., Jordan, L., and Huisman, T. A. (2010). Cerebellar abnormality in children and young adults with tuberous sclerosis complex: MR and diffusion weighted imaging findings. J. Neuroradiol. 37, 231-238. doi: 10.1016/j.neurad.2009.12.006.
51. Fatemi, S. H., Aldinger, K. A., Ashwood, P., Bauman, M. L., Blaha, C. D., Blatt, G. J., et al. (2012). Consensus paper: pathological role of the cerebellum in autism. Cerebellum 11, 777-807. doi: 10.1007/s12311-012-0355-9.
52. Fatemi, S. H., and Folsom, T. D. (2011). 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 2:6. doi: 10.1186/2040-2392-2-6.
53. Fatemi, S. H., Halt, A. R., Realmuto, G., Earle, J., Kist, D. A., Thuras, P., et al. (2002a). Purkinje cell size is reduced in cerebellum of patients with autism. Cell. Mol. Neurobiol. 22, 171-175. doi: 10.1023/A:1019861721160.
54. Fatemi, S. H., Halt, A. R., Stary, J. M., Kanodia, R., Schulz, S. C., and Realmuto, G. R. (2002b). Glutamic acid decarboxylase 65 and 67 kDa proteins are reduced in autistic parietal and cerebellar cortices. Biol. Psychiatry 52, 805-810. doi: 10.1016/S0006-3223(02)01430-0.
55. Filippi, R., Richardson, F. M., Dick, F., Leech, R., Green, D. W., Thomas, M. S., et al. (2011). The right posterior paravermis and the control of language interference. J. Neurosci. 31, 10732-10740. doi: 10.1523/JNEUROSCI.1783-11.2011.
56. Fung, L. K., and Hardan, A. Y. (2014). Autism in DSM-5 under the microscope: implications to patients, families, clinicians, and researchers. Asian J. Psychiatr. 11, 93-97. doi: 10.1016/j.ajp.2014.08.010.
57. Gallagher, A., and Hallahan, B. (2012). Fragile X-associated disorders: a clinical overview. J. Neurol. 259, 401-413. doi: 10.1007/s00415-011-6161-3.
58. Goines, P., Haapanen, L., Boyce, R., Duncanson, P., Braunschweig, D., Delwiche, L., et al. (2011). Autoantibodies to cerebellum in children with autism associate with behavior. Brain Behav. Immun. 25, 514-523. doi: 10.1016/j.bbi.2010.11.017.
59. Gothelf, D., Furfaro, J. A., Hoeft, F., Eckert, M. A., Hall, S. S., O'Hara, R., et al. (2008). Neuroanatomy of fragile X syndrome is associated with aberrant behavior and the fragile X mental retardation protein (FMRP). Ann. Neurol. 63, 40-51.
60. Greco, C. M., Berman, R. F., Martin, R. M., Tassone, F., Schwartz, P. H., Chang, A., et al. (2006). Neuropathology of fragile X-associated tremor/ataxia syndrome (FXTAS). Brain 129, 243-255. doi: 10.1093/brain/awh683.
61. Greco, C. M., Hagerman, R. J., Tassone, F., Chudley, A. E., Del Bigio, M. R., Jacquemont, S., et al. (2002). Neuronal intranuclear inclusions in a new cerebellar tremor/ataxia syndrome among fragile X carriers. Brain 125, 1760-1771. doi: 10.1093/brain/awf184.
62. Greco, C. M., Navarro, C. S., Hunsaker, M. R., Maezawa, I., Shuler, J. F., Tassone, F., et al. (2011). Neuropathologic features in the hippocampus and cerebellum of three older men with fragile X syndrome. Mol. Autism 2:2. doi: 10.1186/2040-2392-2-2.
63. Groenewegen, H. J., Voogd, J., and Freedman, S. L. (1979). The parasagittal zonation within the olivocerebellar projection. II. Climbing fiber distribution in the intermediate and hemispheric parts of cat cerebellum. J. Comp. Neurol. 183, 551-601. doi: 10.1002/cne.901830307.
64. Hagerman, P. J., and Hagerman, R. J. (2015). Fragile X-associated tremor/ataxia syndrome. Ann. N.Y. Acad. Sci. 1338, 58-70. doi: 10.1111/nyas.12693.
65. Halladay, A. K., Bishop, S., Constantino, J. N., Daniels, A. M., Koenig, K., Palmer, K., et al. (2015). Sex and gender differences in autism spectrum disorder: summarizing evidence gaps and identifying emerging areas of priority. Mol. Autism 6:36. doi: 10.1186/s13229-015-0019-y.
66. Hampson, D. R., Gholizadeh, S., and Pacey, L. K. (2012). Pathways to drug development for autism spectrum disorders. Clin. Pharmacol. Ther. 91, 189-200. doi: 10.1038/clpt.2011.245.
67. Hashimoto, T., Tayama, M., Murakawa, K., Yoshimoto, T., Miyazaki, M., Harada, M., et al. (1995). Development of the brainstem and cerebellum in autistic patients. J. Autism Dev. Disord. 25, 1-18.
68. Herculano-Houzel, S. (2010). Coordinated scaling of cortical and cerebellar numbers of neurons. Front. Neuroanat. 4:12. doi: 10.3389/fnana.2010.00012.
69. Hinton, V. J., Brown, W. T., Wisniewski, K., and Rudelli, R. D. (1991). Analysis of neocortex in three males with the fragile X syndrome. Am. J. Med. Genet. 41, 289-294. doi: 10.1002/ajmg.1320410306.
70. Holmes, G. (1917). The symptoms of acute cerebellar injuries due to gunshot injuries. Brain 40, 461-535.
71. Hussman, J. P. (2001). Suppressed GABAergic inhibition as a common factor in suspected etiologies of autism. J. Autism Dev. Disord. 31, 247-248. doi: 10.1023/A:1010715619091.
72. Irwin, S. A., Galvez, R., and Greenough, W. T. (2000). Dendritic spine structural anomalies in fragile-X mental retardation syndrome. Cereb. Cortex 10, 1038-1044. doi: 10.1093/cercor/10.10.1038.
73. Irwin, S. A., Idupulapati, M., Gilbert, M. E., Harris, J. B., Chakravarti, A. B., Rogers, E. J., et al. (2002). Dendritic spine and dendritic field characteristics of layer V pyramidal neurons in the visual cortex of fragile-X knockout mice. Am. J. Med. Genet. 111, 140-146. doi: 10.1002/ajmg.10500.
74. Irwin, S. A., Patel, B., Idupulapati, M., Harris, J. B., Crisostomo, R. A., Larsen, B. P., et al. (2001). Abnormal dendritic spine characteristics in the temporal and visual cortices of patients with fragile-X syndrome: a quantitative examination. Am. J. Med. Genet. 98, 161-167. doi: 10.1002/1096-8628(20010115)98:2%3C161::AID-AJMG1025%3E3.0.CO;2-B.
75. Ito, M. (2008). Control of mental activities by internal models in the cerebellum. Nat. Rev. Neurosci. 9, 304-313. doi: 10.1038/nrn2332.
76. Jurkiewicz, E., Józwiak, S., Bekiesinska-Figatowska, M., Pakiela-Domanska, D., Pakula-Kosciesza, I., and Walecki, J. (2006). Cerebellar lesions in children with tuberous sclerosis complex. Neuroradiol. J. 19, 577-582. doi: 10.1177/197140090601900503.
77. Kalkbrenner, A. E., Schmidt, R. J., and Penlesky, A. C. (2014). Environmental chemical exposures and autism spectrum disorders: a review of the epidemiological evidence. Curr. Probl. Pediatr. Adolesc. Health Care 44, 277-318. doi: 10.1016/j.cppeds.2014.06.001.
78. Kaufmann, W. E., Cooper, K. L., Mostofsky, S. H., Capone, G. T., Kates, W. R., Newschaffer, C. J., et al. (2003). Specificity of cerebellar vermian abnormalities in autism: a quantitative magnetic resonance imaging study. J. Child Neurol. 18, 463-470. doi: 10.1177/08830738030180070501.
79. Kemper, T. L., and Bauman, M. (1998). Neuropathology of infantile autism. J. Neuropathol. Exp. Neurol. 57, 645-652.
80. Kemper, T. L., and Bauman, M. L. (1993). The contribution of neuropathologic studies to the understanding of autism. Neurol. Clin. 11, 175-187.
81. Knuesel, I., Chicha, L., Britschgi, M., Schobel, S. A., Bodmer, M., Hellings, J. A., et al. (2014). Maternal immune activation and abnormal brain development across CNS disorders. Nat. Rev. Neurol. 10, 643-660. doi: 10.1038/nrneurol.2014.187.
82. Kohane, I. S., McMurry, A., Weber, G., MacFadden, D., Rappaport, L., Kunkel, L., et al. (2012). The co-morbidity burden of children and young adults with autism spectrum disorders. PLoS ONE 7:e33224. doi: 10.1371/journal.pone.0033224.
83. Kong, S. W., Sahin, M., Collins, C. D., Wertz, M. H., Campbell, M. G., Leech, J. D., et al. (2014). Divergent dysregulation of gene expression in murine models of fragile X syndrome and tuberous sclerosis. Mol. Autism 5:16. doi: 10.1186/2040-2392-5-16.
84. Lai, M. C., Lombardo, M. V., Chakrabarti, B., and Baron-Cohen, S. (2013). Subgrouping the autism "spectrum": reflections on DSM-5. PLoS Biol. 11:e1001544. doi: 10.1371/journal.pbio.1001544.
85. Lainé, J., and Axelrad, H. (1998). Lugaro cells target basket and stellate cells in the cerebellar cortex. Neuroreport 9, 2399-2403.
86. Levisohn, L., Cronin-Golomb, A., and Schmahmann, J. D. (2000). Neuropsychological consequences of cerebellar tumour resection in children: cerebellar cognitive affective syndrome in a paediatric population. Brain 123 (Pt 5), 1041-1050. doi: 10.1093/brain/123.5.1041.
87. Llinas, R. R., Walton, K. D., and Lang, E. J. (2004). "Cerebellum," in The Synaptic Organization of the Brain (Oxford University Press), 271-310. doi: 10.1093/acprof:oso/9780195159561.003.0007.
88. Manto, M. U. (2010). Cerebellar Disorders. Cambridge, UK: Cambridge University Press.
89. Mariani, J. (1982). Extent of multiple innervation of Purkinje cells by climbing fibers in the olivocerebellar system of weaver, reeler, and staggerer mutant mice. J. Neurobiol. 13, 119-126. doi: 10.1002/neu.480130204.
90. Martin, L. A., Goldowitz, D., and Mittleman, G. (2010). 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. 31, 544-555. doi: 10.1111/j.1460-9568.2009.07073.x.
91. Maski, K. P., Jeste, S. S., and Spence, S. J. (2011). Common neurological co-morbidities in autism spectrum disorders. Curr. Opin. Pediatr. 23, 609-615. doi: 10.1097/MOP.0b013e32834c9282.
92. Matson, J. L., Matson, M. L., and Rivet, T. T. (2007). Social-skills treatments for children with autism spectrum disorders: an overview. Behav. Modif. 31, 682-707. doi: 10.1177/0145445507301650.
93. Mead, J., and Ashwood, P. (2015). Evidence supporting an altered immune response in ASD. Immunol. Lett. 163, 49-55. doi: 10.1016/j.imlet.2014.11.006.
94. Mugnaini, E., Sekerková, G., and Martina, M. (2011). The unipolar brush cell: a remarkable neuron finally receiving deserved attention. Brain Res. Rev. 66, 220-245. doi: 10.1016/j.brainresrev.2010.10.001.
95. Nevison, C. D. (2014). A comparison of temporal trends in United States autism prevalence to trends in suspected environmental factors. Environ. Health 13:73. doi: 10.1186/1476-069X-13-73.
96. Oblak, A. L., Gibbs, T. T., and Blatt, G. J. (2011). Reduced GABAA receptors and benzodiazepine binding sites in the posterior cingulate cortex and fusiform gyrus in autism. Brain Res. 1380, 218-228. doi: 10.1016/j.brainres.2010.09.021.
97. Oldfors, A., Sourander, P., Armstrong, D. L., Percy, A. K., Witt-Engerström, I., and Hagberg, B. A. (1990). Rett syndrome: cerebellar pathology. Pediatr. Neurol. 6, 310-314.
98. Pacey, L. K., Heximer, S. P., and Hampson, D. R. (2009). Increased GABA(B) receptor-mediated signaling reduces the susceptibility of fragile X knockout mice to audiogenic seizures. Mol. Pharmacol. 76, 18-24. doi: 10.1124/mol.109.056127.
99. Pacey, L. K., Xuan, I. C., Guan, S., Sussman, D., Henkelman, R. M., Chen, Y., et al. (2013). Delayed myelination in a mouse model of fragile X syndrome. Hum. Mol. Genet. 22, 3920-3930. doi: 10.1093/hmg/ddt246.
100. Parisi, M. A., and Dobyns, W. B. (2003). Human malformations of the midbrain and hindbrain: review and proposed classification scheme. Mol. Genet. Metab. 80, 36-53. doi: 10.1016/j.ymgme.2003.08.010.
101. Pierce, K., and Courchesne, E. (2001). Evidence for a cerebellar role in reduced exploration and stereotyped behavior in autism. Biol. Psychiatry 49, 655-664. doi: 10.1016/S0006-3223(00)01008-8.
102. Piras, I. S., Haapanen, L., Napolioni, V., Sacco, R., Van de Water, J., and Persico, A. M. (2014). Anti-brain antibodies are associated with more severe cognitive and behavioral profiles in Italian children with Autism Spectrum Disorder. Brain Behav. Immun. 38, 91-99. doi: 10.1016/j.bbi.2013.12.020.
103. Piven, J., Saliba, K., Bailey, J., and Arndt, S. (1997). An MRI study of autism: the cerebellum revisited. Neurology 49, 546-551.
104. Posar, A., and Visconti, P. (2014). To what extent do environmental factors contribute to the occurrence of autism spectrum disorders? J. Pediatr. Neurosci. 9, 297-298. doi: 10.4103/1817-1745.147610.
105. Puro, D. G., and Woodward, D. J. (1977). The climbing fiber system in the Weaver mutant. Brain Res. 129, 141-146.
106. Ramnani, N. (2012). Frontal lobe and posterior parietal contributions to the cortico-cerebellar system. Cerebellum 11, 366-383. doi: 10.1007/s12311-011-0272-3.
107. Reardon, W., Donoghue, V., Murphy, A. M., King, M. D., Mayne, P. D., Horn, N., et al. (2010). Progressive cerebellar degenerative changes in the severe mental retardation syndrome caused by duplication of MECP2 and adjacent loci on Xq28. Eur. J. Pediatr. 169, 941-949. doi: 10.1007/s00431-010-1144-4.
108. Reeber, S. L., Otis, T. S., and Sillitoe, R. V. (2013). New roles for the cerebellum in health and disease. Front. Syst. Neurosci. 7:83. doi: 10.3389/fnsys.2013.00083.
109. Reith, R. M., McKenna, J., Wu, H., Hashmi, S. S., Cho, S. H., Dash, P. K., et al. (2013). Loss of Tsc2 in Purkinje cells is associated with autistic-like behavior in a mouse model of tuberous sclerosis complex. Neurobiol. Dis. 51, 93-103. doi: 10.1016/j.nbd.2012.10.014.
110. Reith, R. M., Way, S., McKenna, J. III., Haines, K., and Gambello, M. J. (2011). Loss of the tuberous sclerosis complex protein tuberin causes Purkinje cell degeneration. Neurobiol. Dis. 43, 113-122. doi: 10.1016/j.nbd.2011.02.014.
111. Riva, D., and Giorgi, C. (2000). The cerebellum contributes to higher functions during development: evidence from a series of children surgically treated for posterior fossa tumours. Brain 123 (Pt 5), 1051-1061. doi: 10.1093/brain/123.5.1051.
112. Rogers, T. D., McKimm, E., Dickson, P. E., Goldowitz, D., Blaha, C. D., and Mittleman, G. (2013). Is autism a disease of the cerebellum? An integration of clinical and pre-clinical research. Front. Syst. Neurosci. 7:15. doi: 10.3389/fnsys.2013.00015.
113. Ropers, H. H., and Hamel, B. C. (2005). X-linked mental retardation. Nat. Rev. Genet. 6, 46-57. doi: 10.1038/nrg1501.
114. Rossi, C. C., Van de Water, J., Rogers, S. J., and Amaral, D. G. (2011). Detection of plasma autoantibodies to brain tissue in young children with and without autism spectrum disorders. Brain Behav. Immun. 25, 1123-1135. doi: 10.1016/j.bbi.2011.02.011.
115. Rubenstein, J. L., and Merzenich, M. M. (2003). Model of autism: increased ratio of excitation/inhibition in key neural systems. Genes Brain Behav. 2, 255-267. doi: 10.1034/j.1601-183X.2003.00037.x.
116. Schmahmann, J. D. (2000). The role of the cerebellum in affect and psychosis. J. Neurolinguistics 13, 189-214. doi: 10.1016/S0911-6044(00)00011-7.
117. Schmahmann, J. D. (2004). Disorders of the cerebellum: ataxia, dysmetria of thought, and the cerebellar cognitive affective syndrome. J. Neuropsychiatry Clin. Neurosci. 16, 367-378. doi: 10.1176/appi.neuropsych.16.3.367.
118. Schmahmann, J. D. (2010). The role of the cerebellum in cognition and emotion: personal reflections since 1982 on the dysmetria of thought hypothesis, and its historical evolution from theory to therapy. Neuropsychol. Rev. 20, 236-260. doi: 10.1007/s11065-010-9142-x.
119. Schmahmann, J. D., and Pandya, D. N. (1989). Anatomical investigation of projections to the basis pontis from posterior parietal association cortices in rhesus monkey. J. Comp. Neurol. 289, 53-73. doi: 10.1002/cne.902890105.
120. Schmahmann, J. D., and Pandya, D. N. (1991). Projections to the basis pontis from the superior temporal sulcus and superior temporal region in the rhesus monkey. J. Comp. Neurol. 308, 224-248. doi: 10.1002/cne.903080209.
121. Schmahmann, J. D., and Pandya, D. N. (1995). Prefrontal cortex projections to the basilar pons in rhesus monkey: implications for the cerebellar contribution to higher function. Neurosci. Lett. 199, 175-178.
122. Schmahmann, J. D., and Pandya, D. N. (1997a). Anatomic organization of the basilar pontine projections from prefrontal cortices in rhesus monkey. J. Neurosci. 17, 438-458.
123. Schmahmann, J. D., and Pandya, D. N. (1997b). The cerebrocerebellar system. Int. Rev. Neurobiol. 41, 31-60.
124. Schmahmann, J. D., and Sherman, J. C. (1998). The cerebellar cognitive affective syndrome. Brain 121 (Pt 4), 561-579.
125. Schumann, C. M., and Nordahl, C. W. (2011). Bridging the gap between MRI and postmortem research in autism. Brain Res. 1380, 175-186. doi: 10.1016/j.brainres.2010.09.061.
126. Scoles, H. A., Urraca, N., Chadwick, S. W., Reiter, L. T., and Lasalle, J. M. (2011). Increased copy number for methylated maternal 15q duplications leads to changes in gene and protein expression in human cortical samples. Mol. Autism 2:19. doi: 10.1186/2040-2392-2-19.
127. Scott, J. A., Schumann, C. M., Goodlin-Jones, B. L., and Amaral, D. G. (2009). A comprehensive volumetric analysis of the cerebellum in children and adolescents with autism spectrum disorder. Autism Res. 2, 246-257. doi: 10.1002/aur.97.
128. Simms, M. L., Kemper, T. L., Timbie, C. M., Bauman, M. L., and Blatt, G. J. (2009). The anterior cingulate cortex in autism: heterogeneity of qualitative and quantitative cytoarchitectonic features suggests possible subgroups. Acta Neuropathol. 118, 673-684. doi: 10.1007/s00401-009-0568-2.
129. Singer, H. S., Morris, C. M., Williams, P. N., Yoon, D. Y., Hong, J. J., and Zimmerman, A. W. (2006). Antibrain antibodies in children with autism and their unaffected siblings. J. Neuroimmunol. 178, 149-155. doi: 10.1016/j.jneuroim.2006.05.025.
130. Skefos, J., Cummings, C., Enzer, K., Holiday, J., Weed, K., Levy, E., et al. (2014). Regional alterations in purkinje cell density in patients with autism. PLoS One. 9:e81255. doi: 10.1371/journal.pone.0081255.
131. Stanfield, A. C., McIntosh, A. M., Spencer, M. D., Philip, R., Gaur, S., and Lawrie, S. M. (2008). Towards a neuroanatomy of autism: a systematic review and meta-analysis of structural magnetic resonance imaging studies. Eur. Psychiatry 23, 289-299. doi: 10.1016/j.eurpsy.2007.05.006.
132. Steadman, P. E., Ellegood, J., Szulc, K. U., Turnbull, D. H., Joyner, A. L., Henkelman, R. M., et al. (2014). Genetic effects on cerebellar structure across mouse models of autism using a magnetic resonance imaging atlas. Autism Res. 7, 124-137. doi: 10.1002/aur.1344.
133. Strick, P. L., Dum, R. P., and Fiez, J. A. (2009). Cerebellum and nonmotor function. Annu. Rev. Neurosci. 32, 413-434. doi: 10.1146/annurev.neuro.31.060407.125606.
134. Sundberg, M., and Sahin, M. (2015). Cerebellar development and autism spectrum disorder in tuberous sclerosis complex. J. Child Neurol. doi: 10.1177/0883073815600870. [Epub ahead of print].
135. Tarquinio, D. C., Hou, W., Neul, J. L., Kaufmann, W. E., Glaze, D. G., Motil, K. J., et al. (2015). The changing face of survival in Rett syndrome and MECP2-related disorders. Pediatr. Neurol. 53, 402-411. doi: 10.1016/j.pediatrneurol.2015.06.003.
136. Tavano, A., Grasso, R., Gagliardi, C., Triulzi, F., Bresolin, N., Fabbro, F., et al. (2007). Disorders of cognitive and affective development in cerebellar malformations. Brain 130, 2646-2660. doi: 10.1093/brain/awm201.
137. Tedesco, A. M., Chiricozzi, F. R., Clausi, S., Lupo, M., Molinari, M., and Leggio, M. G. (2011). The cerebellar cognitive profile. Brain 134, 3672-3686. doi: 10.1093/brain/awr266.
138. Tierney, C., Mayes, S., Lohs, S. R., Black, A., Gisin, E., and Veglia, M. (2015). How valid is the checklist for autism spectrum disorder when a child has apraxia of speech? J. Dev. Behav. Pediatr. 36, 569-574. doi: 10.1097/DBP.0000000000000189.
139. Timmann, D., Konczak, J., Ilg, W., Donchin, O., Hermsdörfer, J., Gizewski, E. R., et al. (2009). Current advances in lesion-symptom mapping of the human cerebellum. Neuroscience 162, 836-851. doi: 10.1016/j.neuroscience.2009.01.040.
140. Tsai, P. T., Hull, C., Chu, Y., Greene-Colozzi, E., Sadowski, A. R., Leech, J. M., et al. (2012). Autistic-like behaviour and cerebellar dysfunction in Purkinje cell Tsc1 mutant mice. Nature 488, 647-651. doi: 10.1038/nature11310.
141. van Kooten, I. A., Palmen, S. J., von Cappeln, P., Steinbusch, H. W., Korr, H., Heinsen, H., et al. (2008). Neurons in the fusiform gyrus are fewer and smaller in autism. Brain 131, 987-999. doi: 10.1093/brain/awn033.
142. Vargas, D. L., Nascimbene, C., Krishnan, C., Zimmerman, A. W., and Pardo, C. A. (2005). Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann. Neurol. 57, 67-81. doi: 10.1002/ana.20315.
143. Vaughn, J., Hagiwara, M., Katz, J., Roth, J., Devinsky, O., Weiner, H., et al. (2013). MRI characterization and longitudinal study of focal cerebellar lesions in a young tuberous sclerosis cohort. Am. J. Neuroradiol. 34, 655-659. doi: 10.3174/ajnr. A3260.
144. Wang, S. S., Kloth, A. D., and Badura, A. (2014). The cerebellum, sensitive periods, and autism. Neuron 83, 518-532. doi: 10.1016/j.neuron.2014.07.016.
145. Way, S. W., McKenna, J. III., Mietzsch, U., Reith, R. M., Wu, H. C., and Gambello, M. J. (2009). Loss of Tsc2 in radial glia models the brain pathology of tuberous sclerosis complex in the mouse. Hum. Mol. Genet. 18, 1252-1265. doi: 10.1093/hmg/ddp025.
146. Weaver, A. H. (2005). Reciprocal evolution of the cerebellum and neocortex in fossil humans. Proc. Natl. Acad. Sci. U.S.A. 102, 3576-3580. doi: 10.1073/pnas.0500692102.
147. Webb, S. J., Sparks, B. F., Friedman, S. D., Shaw, D. W., Giedd, J., Dawson, G., et al. (2009). Cerebellar vermal volumes and behavioral correlates in children with autism spectrum disorder. Psychiatry Res. 172, 61-67. doi: 10.1016/j.pscychresns.2008.06.001.
148. Wegiel, J., Kuchna, I., Nowicki, K., Imaki, H., Wegiel, J., Marchi, E., et al. (2010). The neuropathology of autism: defects of neurogenesis and neuronal migration, and dysplastic changes. Acta Neuropathol. 119, 755-770. doi: 10.1007/s00401-010-0655-4.
149. Weisenfeld, N. I., Peters, J. M., Tsai, P. T., Prabhu, S. P., Dies, K. A., Sahin, M., et al. (2013). A magnetic resonance imaging study of cerebellar volume in tuberous sclerosis complex. Pediatr. Neurol. 48, 105-110. doi: 10.1016/j.pediatrneurol.2012.10.011.
150. Welsh, J. P. (2002). Functional significance of climbing-fiber synchrony: a population coding and behavioral analysis. Ann. N.Y. Acad. Sci. 978, 188-204. doi: 10.1111/j.1749-6632.2002.tb07567.x.
151. Welsh, J. P., Ahn, E. S., and Placantonakis, D. G. (2005). Is autism due to brain desynchronization? Int. J. Dev. Neurosci. 23, 253-263. doi: 10.1016/j.ijdevneu.2004.09.002.
152. Whitney, E. R., Kemper, T. L., Bauman, M. L., Rosene, D. L., and Blatt, G. J. (2008). Cerebellar Purkinje cells are reduced in a subpopulation of autistic brains: a stereological experiment using calbindin-D28k. Cerebellum 7, 406-416. doi: 10.1007/s12311-008-0043-y.
153. Wills, S., Cabanlit, M., Bennett, J., Ashwood, P., Amaral, D. G., and Van de Water, J. (2009). Detection of autoantibodies to neural cells of the cerebellum in the plasma of subjects with autism spectrum disorders. Brain Behav. Immun. 23, 64-74. doi: 10.1016/j.bbi.2008.07.007.
154. Wills, S., Rossi, C. C., Bennett, J., Martinez Cerdeño, V., Ashwood, P., Amaral, D. G., et al. (2011). Further characterization of autoantibodies to GABAergic neurons in the central nervous system produced by a subset of children with autism. Mol. Autism 2:5. doi: 10.1186/2040-2392-2-5.
155. Yip, J., Soghomonian, J. J., and Blatt, G. J. (2007). Decreased GAD67 mRNA levels in cerebellar Purkinje cells in autism: pathophysiological implications. Acta Neuropathol. 113, 559-568. doi: 10.1007/s00401-006-0176-3.
156. Yip, J., Soghomonian, J. J., and Blatt, G. J. (2008). Increased GAD67 mRNA expression in cerebellar interneurons in autism: implications for Purkinje cell dysfunction. J. Neurosci. Res. 86, 525-530. doi: 10.1002/jnr.21520.
157. Yip, J., Soghomonian, J. J., and Blatt, G. J. (2009). Decreased GAD65 mRNA levels in select subpopulations of neurons in the cerebellar dentate nuclei in autism: an in situ hybridization study. Autism Res. 2, 50-59. doi: 10.1002/aur.62.
158. Zafeiriou, D. I., Ververi, A., Dafoulis, V., Kalyva, E., and Vargiami, E. (2013). Autism spectrum disorders: the quest for genetic syndromes. Am. J. Med. Genet. B Neuropsychiatr. Genet. 162B, 327-366. doi: 10.1002/ajmg.b.32152.
159. Zimmerman, A. W., Connors, S. L., Matteson, K. J., Lee, L. C., Singer, H. S., Castaneda, J. A., et al. (2007). Maternal antibrain antibodies in autism. Brain Behav. Immun. 21, 351-357. doi: 10.1016/j.bbi.2006.08.005.