Motor Circuit Abnormalities During Cerebellar Development

  • Elizabeth P. Lackey
  • Roy V. SillitoeEmail author
Part of the Contemporary Clinical Neuroscience book series (CCNE)


The cerebellum controls ongoing motor function and motor learning. Therefore, damage to its circuits causes a number of movement disorders such as ataxia, dystonia, and tremor. Cerebellar connectivity in both normal and abnormal states has been intensely studied. As a result, its anatomy, circuitry, and neuronal firing properties are among the best understood in the brain. This knowledge has directly facilitated efforts to uncover the mechanisms that cause motor dysfunction. Here, we discuss several mouse models of cerebellar disease. We focus on how cerebellar development depends on genes and neural activity to assemble circuits for behavior.


Cerebellum Circuitry Ataxia Purkinje cell Cerebellar nuclei Inferior olive 



This work was supported by funds from Baylor College of Medicine (BCM) and Texas Children’s Hospital. R.V.S. received support from the National Institutes of Neurological Disorders and Stroke (NINDS) R01NS089664. The BCM IDDRC Neuropathology Sub-Core performed the tissue staining (the BCM IDDRC Neurovisualization Core is supported by U54HD083092). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health (NIH). We thank Amanda M. Brown for suggestions and comments on an earlier version of the manuscript.


  1. 1.
    Gilbert PFC, Thach WT. Purkinje cell activity during motor learning. Brain Res. 1977;128(2):309–28.PubMedCrossRefPubMedCentralGoogle Scholar
  2. 2.
    Llinás RR. The olivo-cerebellar system: a key to understanding the functional significance of intrinsic oscillatory brain properties. Front Neural Circuits. 2013;7:96.PubMedPubMedCentralGoogle Scholar
  3. 3.
    Flourens M. Recherches expérimentales sur les propriétés et les fonctions du système nerveux dans les animaux vertébrés. Paris: Crevot; 1824.Google Scholar
  4. 4.
    Babinski J. De l’asynergie cérébelleuse. Rev Neurol. 1899;6:806–16.Google Scholar
  5. 5.
    Babinski J. Sur le rôle du cervelet dans les actes volitionnels nécessitant une succession rapide de mouvements (diadococinésie). Rev Neurol. 1902;10:1013–5.Google Scholar
  6. 6.
    Babinski J. Asynergie et inertie cérébelleuse. Rev Neurol. 1906;14:685–6.Google Scholar
  7. 7.
    Holmes G. The cerebellum of man. Brain. 1939;62:2–30.CrossRefGoogle Scholar
  8. 8.
    Manto M. The cerebellum, cerebellar disorders, and cerebellar research – two centuries of discoveries. Cerebellum. 2008;7(4):505–16.PubMedCrossRefPubMedCentralGoogle Scholar
  9. 9.
    Larsell O. In: Jansen J, editor. The comparative anatomy and histology of the cerebellum from monotremes through apes. Minneapolis: University of Minnesota Press; 1970. p. 31–58.Google Scholar
  10. 10.
    Cajal S. Histologie du Systeme Nerveux de l’Homme et des Vertebres, vol. 2. Madrid: Consejo Superior de Investigaciones Cientificas; 1911.Google Scholar
  11. 11.
    Altman J, Bayer S. Development of the cerebellar system: in relation to its evolution, structure, and functions. Boca Raton: CRC Press; 1997.Google Scholar
  12. 12.
    Sillitoe RV, Joyner AL. Morphology, molecular codes, and circuitry produce the three-dimensional complexity of the cerebellum. Annu Rev Cell Dev Biol. 2007;23:549–77.PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Reeber SL, Otis TS, Sillitoe RV. New roles for the cerebellum in health and disease. Front Syst Neurosci. 2013;7:83.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Fu Y, Tvrdik P, Makki N, Paxinos G, Watson C. Precerebellar cell groups in the hindbrain of the mouse defined by retrograde tracing and correlated with cumulative Wnt1-cre genetic labeling. Cerebellum. 2011;10(3):570–84.PubMedCrossRefGoogle Scholar
  15. 15.
    Schweighofer N, Doya K, Kuroda S. Cerebellar aminergic neuromodulation: towards a functional understanding. Brain Res Rev. 2004;44(2–3):103–16.PubMedCrossRefGoogle Scholar
  16. 16.
    Reeber SL, Sillitoe RV. Patterned expression of a cocaine- and amphetamine-regulated transcript peptide reveals complex circuit topography in the rodent cerebellar cortex. J Comp Neurol. 2011;519(9):1781–96.PubMedCrossRefGoogle Scholar
  17. 17.
    Barmack NH, Yakhnitsa V. Cerebellar climbing fibers modulate simple spikes in Purkinje cells. J Neurosci. 2003;23(21):7904–16.PubMedCrossRefGoogle Scholar
  18. 18.
    Brochu G, Maler L, Hawkes R. Zebrin II: a polypeptide antigen expressed selectively by Purkinje cells reveals compartments in rat and fish cerebellum. J Comp Neurol. 1990;291(4):538–52.CrossRefGoogle Scholar
  19. 19.
    Eisenman LM, Hawkes R. Antigenic compartmentation in the mouse cerebellar cortex: zebrin and HNK-1 reveal a complex, overlapping molecular topography. J Comp Neurol. 1993;335(4):586–605.PubMedCrossRefGoogle Scholar
  20. 20.
    Armstrong C, Hawkes R. Pattern formation in the cerebellar cortex. Biochem Cell Biol. 2000;78(5):551–62.PubMedCrossRefGoogle Scholar
  21. 21.
    Sillitoe RV, Hawkes R, Sillitoe RV, Hawkes R. Screen for patterning defects in the mouse cerebellum. J Histochem Cytochem. 2002;50(2):235–44.PubMedCrossRefGoogle Scholar
  22. 22.
    Sillitoe RV, Marzban H, Larouche M, Zahedi S, Affanni J, Hawkes R. Conservation of the architecture of the anterior lobe vermis of the cerebellum across mammalian species. Prog Brain Res. 2005;148:283–97.PubMedCrossRefGoogle Scholar
  23. 23.
    Pakan J, Iwaniuk A, Wylie D, Hawkes R, Marzban H. Purkinje cell compartmentation as revealed by zebrin II expression in the cerebellar cortex of pigeons (Columba livia). J Comp Neurol. 2007;501(4):619–30.PubMedCrossRefGoogle Scholar
  24. 24.
    Marzban H, Chung SH, Pezhouh MK, Feirabend H, Watanabe M, Voogd J, et al. Antigenic compartmentation of the cerebellar cortex in the chicken (Gallus domesticus). J Comp Neurol. 2010;518(12):2221–39.PubMedCrossRefGoogle Scholar
  25. 25.
    Marzban H, Hawkes R. On the architecture of the posterior zone of the cerebellum. Cerebellum. 2011;10(3):422–34.PubMedCrossRefGoogle Scholar
  26. 26.
    Marzban H, Hoy N, Marotte L, Hawkes R. Antigenic compartmentation of the cerebellar cortex in an Australian marsupial, the tammar wallaby Macropus eugenii. Brain Behav Evol. 2012;80(3):196–209.PubMedCrossRefGoogle Scholar
  27. 27.
    Marzban H, Hoy N, Buchok M, Catania KC, Hawkes R. Compartmentation of the cerebellar cortex: adaptation to lifestyle in the star-nosed mole Condylura cristata. Cerebellum. 2015;14(2):106–18.PubMedCrossRefGoogle Scholar
  28. 28.
    Wylie D, Hoops D, Aspden J, Iwaniuk A. Zebrin II is expressed in sagittal stripes in the cerebellum of dragon lizards (Ctenophorus sp.). Brain Behav Evol. 2017;88(3-4):177–86.CrossRefGoogle Scholar
  29. 29.
    Hawkes R. Purkinje cell stripes and long-term depression at the parallel fiber-Purkinje cell synapse. Front Syst Neurosci. 2014;8:41.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Ozol K, Hayden JM, Oberdick J, Hawkes R. Transverse zones in the vermis of the mouse cerebellum. J Comp Neurol. 1999;412(1):95–111.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Apps R, Hawkes R. Cerebellar cortical organization: a one-map hypothesis. Nat Rev Neurosci. 2009;10(9):670–81.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Ji Z, Hawkes R. Developing mossy fiber terminal fields in the rat cerebellar cortex may segregate because of Purkinje cell compartmentation and not competition. J Comp Neurol. 1995;359(2):197–212.PubMedCrossRefGoogle Scholar
  33. 33.
    Voogd J, Pardoe J, Ruigrok TJH, Apps R. The distribution of climbing and mossy fiber collateral branches from the copula pyramidis and the paramedian lobule: congruence of climbing fiber cortical zones and the pattern of zebrin banding within the rat cerebellum. J Neurosci. 2003;23(11):4645–56.CrossRefGoogle Scholar
  34. 34.
    Hesslow G. Correspondence between climbing fibre input and motor output in eyeblink-related areas in cat cerebellar cortex. J Physiol. 1994;476(2):229–44.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Ekerot CF, Larson B. Branching of olivary axons to innervate pairs of sagittal zones in the cerebellar anterior lobe of the cat. Exp Brain Res. 1982;48(2):185–98.PubMedCrossRefGoogle Scholar
  36. 36.
    Apps R, Trott JR, Dietrichs E. A study of branching in the projection from the inferior olive to the x and lateral c1 zones of the cat cerebellum using a combined electrophysiological and retrograde fluorescent double-labelling technique. Exp Brain Res. 1991;87(1):141–52.PubMedCrossRefGoogle Scholar
  37. 37.
    Ji Z. Topography of Purkinje cell compartments and mossy fiber terminal fields in lobules II and III of the rat cerebellar cortex: spinocerebellar and cuneocerebellar projections. Neuroscience. 1994;61(4):935–54.CrossRefGoogle Scholar
  38. 38.
    Serapide MF, Pantó MR, Parenti R, Zappalá A, Cicirata F. Multiple zonal projections of the basilar pontine nuclei to the cerebellar cortex of the rat. J Comp Neurol. 2001;430(4):471–84.PubMedCrossRefGoogle Scholar
  39. 39.
    Gerrits NM, Voogd J, Nas WSC. Cerebellar and olivary projections of the external and rostral internal cuneate nuclei in the cat. Exp Brain Res. 1985;57(2):239–55.PubMedCrossRefGoogle Scholar
  40. 40.
    Wu HS, Sugihara I, Shinoda Y. Projection patterns of single mossy fibers originating from the lateral reticular nucleus in the rat cerebellar cortex and nuclei. J Comp Neurol. 1999;411(1):97–118.PubMedPubMedCentralGoogle Scholar
  41. 41.
    Kelly RM, Strick PL. Cerebellar loops with motor cortex and prefrontal cortex of a nonhuman primate. J Neurosci. 2003;23(23):8432–44.PubMedCrossRefGoogle Scholar
  42. 42.
    Dum RP, Strick PL. An unfolded map of the cerebellar dentate nucleus and its projections to the cerebral cortex. J Neurophysiol. 2003;89(1):634–9.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Voogd J, Ruigrok TJH. The organization of the corticonuclear and olivocerebellar climbing fiber projections to the rat cerebellar vermis: the congruence of projection zones and the zebrin pattern. J Neurocytol. 2004;33:5–21.CrossRefGoogle Scholar
  44. 44.
    Pijpers A, Voogd J, Ruigrok TJH. Topography of olivo-cortico-nuclear modules in the intermediate cerebellum of the rat. J Comp Neurol. 2005;492(2):193–213.PubMedCrossRefGoogle Scholar
  45. 45.
    Ruigrok TJH. Ins and outs of cerebellar modules. Cerebellum. 2011;10(3):464–74.PubMedCrossRefGoogle Scholar
  46. 46.
    Ruigrok TJH, Pijpers A, Goedknegt-Sabel E, Coulon P. Multiple cerebellar zones are involved in the control of individual muscles: a retrograde transneuronal tracing study with rabies virus in the rat. Eur J Neurosci. 2008;28(1):181–200.PubMedCrossRefGoogle Scholar
  47. 47.
    Chockkan V, Hawkes R. Functional and antigenic maps in the rat cerebellum: zebrin compartmentation and vibrissal receptive fields in lobule IXa. J Comp Neurol. 1994;345(1):33–45.PubMedCrossRefGoogle Scholar
  48. 48.
    Ebner TJ, Chen G, Gao W, Reinert K. Optical imaging of cerebellar functional architectures: parallel fiber beams, parasagittal bands and spreading acidification. Prog Brain Res. 2004;148:125–38.CrossRefGoogle Scholar
  49. 49.
    Wadiche JI, Jahr CE. Patterned expression of Purkinje cell glutamate transporters controls synaptic plasticity. Nat Neurosci. 2005;8(10):1329–34.PubMedCrossRefGoogle Scholar
  50. 50.
    Schonewille M, Luo C, Ruigrok TJ, Voogd J, Schmolesky M, Rutteman M, Freek HE, de Jeu MTG, de Zeeuw CI. Zonal organization of the mouse flocculus: physiology, input, and output. J Comp Neurol. 2006;487:670–82.PubMedCrossRefGoogle Scholar
  51. 51.
    Shambes G, Gibson J, Welker W. Fractured somatotopy in granule cell tactile areas of rat cerebellar hemispheres revealed by micromapping. Brain Behav Evol. 1978;15(2):94–140.PubMedCrossRefGoogle Scholar
  52. 52.
    Hallem JS, Thompson JH, Gundappa-Sulur G, Hawkes R, Bjaalie JG, Bower JM. Spatial correspondence between tactile projection patterns and the distribution of the antigenic Purkinje cell markers anti-zebrin I and anti-zebrin II in the cerebellar folium crus IIa of the rat. Neuroscience. 1999;93(3):1083–94.PubMedCrossRefGoogle Scholar
  53. 53.
    Cerminara NL, Lang EJ, Sillitoe RV, Apps R. Redefining the cerebellar cortex as an assembly of non-uniform Purkinje cell microcircuits. Nat Rev Neurosci. 2015;16(2):79–93.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    White JJ, Sillitoe RV. Development of the cerebellum: from gene expression patterns to circuit maps. Wiley Interdiscip Rev Dev Biol. 2013;2(1):149–64.PubMedCrossRefGoogle Scholar
  55. 55.
    Sudarov A, Joyner AL. Cerebellum morphogenesis: the foliation pattern is orchestrated by multi-cellular anchoring centers. Neural Dev. 2007;2:26.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Lewis PM, Gritli-Linde A, Smeyne R, Kottmann A, McMahon AP. Sonic hedgehog signaling is required for expansion of granule neuron precursors and patterning of the mouse cerebellum. Dev Biol. 2004;270(2):393–410.PubMedPubMedCentralGoogle Scholar
  57. 57.
    Corrales JD, Blaess S, Mahoney EM, Joyner AL. The level of sonic hedgehog signaling regulates the complexity of cerebellar foliation. Development. 2006;133(9):1811–21.PubMedPubMedCentralGoogle Scholar
  58. 58.
    Joyner AL, Herrup K, Auerbach BA, Davis CA, Rossant J. Subtle cerebellar phenotype in mice homozygous for a targeted deletion of the En-2 homeobox. Science. 1991;251(4998):1239–43.PubMedCrossRefGoogle Scholar
  59. 59.
    Kuemerle B, Zanjani H, Joyner A, Herrup K. Pattern deformities and cell loss in Engrailed-2 mutant mice suggest two separate patterning events during cerebellar development. J Neurosci. 1997;17(20):7881–9.PubMedCrossRefGoogle Scholar
  60. 60.
    Oberdick J, Schilling K, Smeyne R, Corbin J, Bocchiaro C, Morgan J. Control of segment-like patterns of gene expression in the mouse cerebellum. Neuron. 1993;10(6):1007–18.PubMedCrossRefPubMedCentralGoogle Scholar
  61. 61.
    Millen KJ, Hui CC, Joyner AL. A role for En-2 and other murine homologues of Drosophila segment polarity genes in regulating positional information in the developing cerebellum. Development. 1995;121(12):3935–45.PubMedGoogle Scholar
  62. 62.
    Larouche M, Hawkes R. From clusters to stripes: the developmental origins of adult cerebellar compartmentation. Cerebellum. 2006;5(2):77–88.PubMedCrossRefGoogle Scholar
  63. 63.
    Arndt K, Nakagawa S, Takeichi M, Redies C. Cadherin-defined segments and parasagittal cell ribbons in the developing chicken cerebellum. Mol Cell Neurosci. 1998;10(5–6):211–28.PubMedCrossRefPubMedCentralGoogle Scholar
  64. 64.
    Luo J, Treubert-Zimmermann U, Redies C. Cadherins guide migrating Purkinje cells to specific parasagittal domains during cerebellar development. Mol Cell Neurosci. 2004;25(1):138–52.PubMedCrossRefGoogle Scholar
  65. 65.
    Hashimoto M, Mikoshiba K. Mediolateral compartmentalization of the cerebellum is determined on the “birth date” of Purkinje cells. J Neurosci. 2003;23(36):11342–51.PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Ashwell K, Zhang L. Ontogeny of afferents to the fetal rat cerebellum. Acta Anat. 1992;145(1):17–23.PubMedCrossRefGoogle Scholar
  67. 67.
    Grishkat H, LM E. Development of the spinocerebellar projection in the prenatal mouse. J Comp Neurol. 1995;363(1):93–108.CrossRefGoogle Scholar
  68. 68.
    Paradies MA, Eisenman LM. Evidence of early topographic organization in the embryonic olivocerebellar projection: a model system for the study of pattern formation processes in the central nervous system. Dev Dyn. 1993;197(2):125–45.PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Paradies MA, Grishkat H, Smeyne RJ, Oberdick J, Morgan JI, Eisenman LM. Correspondence between L7-lacZ-expressing Purkinje cells and labeled olivocerebellar fibers during late embryogenesis in the mouse. J Comp Neurol. 1996;374(3):451–66.CrossRefGoogle Scholar
  70. 70.
    Arsénio Nunes M, Sotelo C, Wehrlé R. Organization of spinocerebellar projection map in three types of agranular cerebellum: Purkinje cells vs. granule cells as organizer element. J Comp Neurol. 1988;273(1):120–36.PubMedCrossRefPubMedCentralGoogle Scholar
  71. 71.
    Sotelo C, Wassef M. Cerebellar development: afferent organization and Purkinje cell heterogeneity. Philos Trans R Soc Lond Ser B Biol Sci. 1991;331:307–13.CrossRefGoogle Scholar
  72. 72.
    Sillitoe RV, Vogel MW, Joyner AL. Engrailed homeobox genes regulate establishment of the cerebellar afferent circuit map. J Neurosci. 2010;30(30):10015–24.PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Sillitoe RV. Mossy fibers terminate directly within Purkinje cell zones during mouse development. Cerebellum. 2016;15(1):14–7.PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Arsénio NM, Sotelo C. Development of the spinocerebellar system in the postnatal rat. J Comp Neurol. 1985;237(3):291–306.CrossRefGoogle Scholar
  75. 75.
    Watanabe M, Kano M. Climbing fiber synapse elimination in cerebellar Purkinje cells. Eur J Neurosci. 2011;34(10):1697–710.PubMedCrossRefPubMedCentralGoogle Scholar
  76. 76.
    Arancillo M, White JJ, Lin T, Stay TL, Sillitoe RV. In vivo analysis of Purkinje cell firing properties during postnatal mouse development. J Neurophysiol. 2015;113(2):578–91.PubMedCrossRefPubMedCentralGoogle Scholar
  77. 77.
    Leto K, Arancillo M, Becker EBE, Buffo A, Chiang C, Ding B, Dobyns WB, Dusart I, Haldipur P, Hatten ME, Hoshino M, Joyner AL, Kano M, Kilpatrick DL, Koibuchi N, Marino S, Martinez S, Millen KJ, Millner TO, Miyata T, Parmigiani E, Schilling K, Sekerkova G, Sillitoe RV, Sotelo C, Uesaka N, Wefers A, Wingate RJT, Hawkes R. Consensus paper: cerebellar development. Cerebellum. 2016;15:789–828.CrossRefGoogle Scholar
  78. 78.
    Sgaier SK, Lao Z, Villanueva MP, Berenshteyn F, Stephen D, Turnbull RK, Joyner AL. Genetic subdivision of the tectum and cerebellum into functionally related regions based on differential sensitivity to engrailed proteins. Development. 2007;134(12):2325–35.PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Sillitoe RV, Stephen D, Lao Z, Joyner AL. Engrailed homeobox genes determine the organization of Purkinje cell sagittal stripe gene expression in the adult cerebellum. J Neurosci. 2008;28(47):12150–62.PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Cheng Y, Sudarov A, Szulc KU, Sgaier SK, Stephen D, Turnbull DH, Joyner AL. The Engrailed homeobox genes determine the different foliation patterns in the vermis and hemispheres of the mammalian cerebellum. Development. 2010;137(3):519–29.PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Millen KJ, Wurst W, Herrup K, Joyner AL. Abnormal embryonic cerebellar development and patterning of postnatal foliation in two mouse Engrailed-2 mutants. Development. 1994;120(3):695–706.PubMedPubMedCentralGoogle Scholar
  82. 82.
    Sillitoe RV, George-Jones NA, Millen KJ, Hawkes R. Purkinje cell compartmentalization in the cerebellum of the spontaneous mutant mouse dreher. Brain Struct Funct. 2014;219(1):35–47.PubMedCrossRefGoogle Scholar
  83. 83.
    Beierbach E, Park C, Ackerman S, Goldowitz D, Hawkes R. Abnormal dispersion of a purkinje cell subset in the mouse mutant cerebellar deficient folia (cdf). J Comp Neurol. 2001;436(1):42–51.PubMedCrossRefGoogle Scholar
  84. 84.
    Reeber SL, Loeschel CA, Franklin A, Sillitoe RV. Establishment of topographic circuit zones in the cerebellum of scrambler mutant mice. Front Neural Circ. 2013;7:122.Google Scholar
  85. 85.
    Vig J, Goldowitz D, Steindler DA, Eisenman LM. Compartmentation of the reeler cerebellum: segregation and overlap of spinocerebellar and secondary vestibulocerebellar fibers and their target cells. Neuroscience. 2005;130(3):735–44.PubMedCrossRefGoogle Scholar
  86. 86.
    Goffinet AM, So KF, Yamamoto M, Edwards M, Caviness VS. Architectonic and hodological organization of the cerebellum in reeler mutant mice. Dev Brain Res. 1984;16(2):263–76.CrossRefGoogle Scholar
  87. 87.
    Bodranghien F, Bastian A, Casali C, Hallett M, Louis ED, Manto M, Marien P, Nowak DA, Schmahmann JD, Serrao M, Steiner KM, Strupp M, Tilikete C, Timmann D, van Dun K, Consensus paper: revisiting the symptoms and signs of cerebellar syndrome. Cerebellum. 2016;15(3):369–91.CrossRefGoogle Scholar
  88. 88.
    Durr A. Autosomal dominant cerebellar ataxias: polyglutamine expansions and beyond. Lancet Neurol. 2010;9(9):885–94.PubMedCrossRefPubMedCentralGoogle Scholar
  89. 89.
    Klockgether T. Sporadic ataxia with adult onset: classification and diagnostic criteria. Lancet Neurol. 2010;9(1):94–104.PubMedCrossRefPubMedCentralGoogle Scholar
  90. 90.
    Zoghbi HY, Orr HT. Spinocerebellar ataxia type 1. Semin Cell Biol. 1995;6(1):29–35.PubMedCrossRefGoogle Scholar
  91. 91.
    Orr H, Chung M, Banfi S, Kwiatkowski TJ, Servadio A, Beaudet A, McCall AE, Duvick LA, Ranum LPW, Zoghbi HY. Expansion of an unstable trinucleotide CAG repeat in spinocerebellar ataxia type 1. Nat Genet. 1993;4(3):221–6.PubMedCrossRefGoogle Scholar
  92. 92.
    Gilman S, Sima A, Junck L, Kluin K, Koeppe R, Lohman M, Little R. Spinocerebellar ataxia type 1 with multiple system degeneration and glial cytoplasmic inclusions. Ann Neurol. 1996;39(2):241–55.PubMedCrossRefGoogle Scholar
  93. 93.
    Lim J, Crespo-barreto J, Jafar-nejad P, Bowman AB, Richman R, Hill DE, Orr HT, Zoghbi HY. Opposing effects of polyglutamine expansion on native protein complexes contribute to SCA1. Nature. 2008;452(7188):713–8.PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Zoghbi HY, Orr HT. Glutamine repeats and neurodegeneration. Annu Rev Neurosci. 2000;23:217–47.PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Koeppen A. The Purkinje cell and its afferents in human hereditary ataxia. J Neuropathol Exp Neurol. 1991;50(4):505–14.PubMedCrossRefGoogle Scholar
  96. 96.
    Ferrer I, Genís D, Dávalos A, Bernadó L, Sant F, Serrano T. The Purkinje cell in olivopontocerebellar atrophy. A Golgi and immunocytochemical study. Neuropathol Appl Neurobiol. 1994;20(1):38–46.PubMedCrossRefGoogle Scholar
  97. 97.
    Clark H, Burright E, Yunis W, Larson S, Wilcox C, Hartman B, Matilla A, Zoghbi HY, Orr HT. Purkinje cell expression of a mutant allele of SCA1 in transgenic mice leads to disparate effects on motor behaviors, followed by a progressive cerebellar dysfunction and histological alterations. J Neurosci. 1997;17(19):7385–95.PubMedCrossRefGoogle Scholar
  98. 98.
    Burright EN, Brent Clark H, Servadio A, Matilla T, Feddersen RM, Yunis WS, Duvick LA, Zoghbi HY, Orr HT. SCA1 transgenic mice: a model for neurodegeneration caused by an expanded CAG trinucleotide repeat. Cell. 1995;82(6):937–48.PubMedCrossRefGoogle Scholar
  99. 99.
    Watase K, Weeber EJ, Xu B, Antalffy B, Yuva-Paylor L, Hashimoto K, Kano M, Atkinson R, Sun Y, Armstrong DL, Sweatt JD, Orr HT, Paylor R, Zoghbi HY. A long CAG repeat in the mouse Sca1 locus replicates SCA1 features and reveals the impact of protein solubility on selective neurodegeneration. Neuron. 2002;34(6):905–19.PubMedCrossRefGoogle Scholar
  100. 100.
    Hourez R, Servais L, Orduz D, Gall D, Millard I, de Kerchove d’Exaerde A, Cheron G, Orr HT, Pandolfo M, Schiffmann SN. Aminopyridines correct early dysfunction and delay neurodegeneration in a mouse model of spinocerebellar ataxia type 1. J Neurosci. 2011;31(33):11795–807.PubMedCrossRefGoogle Scholar
  101. 101.
    Dell’Orco JM, Wasserman AH, Chopra R, Ingram MAC, Hu Y-S, Singh V, Wulff H, Opal P, Shakkottai VG. Neuronal atrophy early in degenerative ataxia is a compensatory mechanism to regulate membrane excitability. J Neurosci. 2015;35(32):11292–307.PubMedCrossRefGoogle Scholar
  102. 102.
    Serra HG, Byam CE, Lande JD, Tousey SK, Zoghbi HY, Orr HT. Gene profiling links SCA1 pathophysiology to glutamate signaling in Purkinje cells of transgenic mice. Hum Mol Genet. 2004;13(20):2535–43.PubMedCrossRefGoogle Scholar
  103. 103.
    Lin X, Antalffy B, Kang D, Orr HT, Zoghbi HY. Polyglutamine expansion down-regulates specific neuronal genes before pathologic changes in SCA1. Nat Neurosci. 2000;3(2):157–63.PubMedCrossRefGoogle Scholar
  104. 104.
    Zhuchenko O, Bailey J, Bonnen P, Ashizawa T, Stockton DW, Amos C, Dobyns WB, Subramony SH, Zoghbi HY, Lee CC. Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansion in the α1A-voltage-dependent calcium channel. Nat Genet. 1997;15:62–9.PubMedCrossRefGoogle Scholar
  105. 105.
    Ishikawa K, Watanabe M, Shoji S, Tsuji S. Japanese families with autosomal dominant pure cerebellar ataxia map to chromosome 19p13.1-p13.2 and are strongly associated with mild CAG expansions in the spinocerebellar ataxia type 6 gene in chromosome 19p13.1. Am Soc Hum Genet. 1997:336–46.PubMedCrossRefGoogle Scholar
  106. 106.
    Yang Q, Hashizume Y, Yoshida M, Wang Y, Goto Y, Mitsuma N, Ishikawa K, Mizusawa H. Morphological Purkinje cell changes in spinocerebellar ataxia type 6. Acta Neuropathol. 2000;100(4):371–6.PubMedCrossRefGoogle Scholar
  107. 107.
    Westenbroek RE, Sakurai T, Elliott EM, Hell JW, Starr TV, Snutch TP, Catterall WA. Immunochemical identification and subcellular distribution of the alpha 1A subunits of brain calcium channels. J Neurosci. 1995;15(10):6403–18.PubMedCrossRefGoogle Scholar
  108. 108.
    Schols L, Kruger R, Amoiridis G, Przuntek H, Epplen JT, Riess O. Spinocerebellar ataxia type 6: genotype and phenotype in German kindreds. J Neurol Neurosurg Psychiatry. 1998;64(1):67–73.PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Tsuchiya K, Oda T, Yoshida M, Sasaki H, Haga C, Okino H, Tominaga I, Matsui K, Akiyama H, Hashizume Y. Degeneration of the inferior olive in spinocerebellar ataxia 6 may depend on disease duration: report of two autopsy cases and statistical analysis of autopsy cases reported to date. Neuropathology. 2005;25(2):125–35.PubMedCrossRefGoogle Scholar
  110. 110.
    Stefanescu MR, Dohnalek M, Maderwald S, Thürling M, Minnerop M, Beck A, Schlamann M, Diedrichsen J, Ladd ME, Timmann D. Structural and functional MRI abnormalities of cerebellar cortex and nuclei in SCA3, SCA6 and Friedreich’s ataxia. Brain. 2015;138(Pt 5):1182–97.PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Jayabal S, Ljungberg L, Erwes T, Cormier A, Quilez S, El Jaouhari S, Watt AJ. Rapid onset of motor deficits in a mouse model of spinocerebellar ataxia type 6 precedes late cerebellar degeneration. eNeuro. 2015;2(6):ENEURO. 0094–15.2015.Google Scholar
  112. 112.
    Jayabal S, Chang HHV, Cullen KE, Watt AJ. 4-Aminopyridine reverses ataxia and cerebellar firing deficiency in a mouse model of spinocerebellar ataxia type 6. Sci Rep. 2016;6:29489.PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Mark MD, Krause M, Boele HJ, Kruse W, Pollok S, Kuner T, Dalkara D, Koekkoek S, De Zeeuw CI, Herlitze S. Spinocerebellar ataxia type 6 protein aggregates cause deficits in motor learning and cerebellar plasticity. J Neurosci. 2015;35(23):8882–95.PubMedCrossRefPubMedCentralGoogle Scholar
  114. 114.
    Womack MD, Chevez C, Khodakhah K. Calcium-activated potassium channels are selectively coupled to P/Q-type calcium channels in cerebellar Purkinje neurons. J Neurosci. 2004;24(40):8818–22.PubMedCrossRefPubMedCentralGoogle Scholar
  115. 115.
    Watase K, Barrett CF, Miyazaki T, Ishiguro T, Ishikawa K, Hu Y, Unno T, Sun Y, Kasai S, Watanabe M, Gomez CM, Mizusawa H, Tsien RW, Zoghbi HY. Spinocerebellar ataxia type 6 knockin mice develop a progressive neuronal dysfunction with age-dependent accumulation of mutant CaV2.1 channels. Proc Natl Acad Sci U S A. 2008;105(33):11987–92.CrossRefGoogle Scholar
  116. 116.
    Saegusa H, Wakamori M, Matsuda Y, Wang J, Mori Y, Zong S, Tanabe T. Properties of human Cav2.1 channel with a spinocerebellar ataxia type 6 mutation expressed in Purkinje cells. Mol Cell Neurosci. 2007;34(2):261–70.PubMedCrossRefPubMedCentralGoogle Scholar
  117. 117.
    Indriati DW, Kamasawa N, Matsui K, Meredith AL, Watanabe M, Shigemoto R. Quantitative localization of Cav2.1 (P/Q-type) voltage-dependent calcium channels in Purkinje cells: somatodendritic gradient and distinct somatic coclustering with calcium-activated potassium channels. J Neurosci. 2013;33(8):3668–78.PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Miyazaki T. P/Q-type Ca2+ channel 1A regulates synaptic competition on developing cerebellar Purkinje cells. J Neurosci. 2004;24(7):1734–43.PubMedCrossRefPubMedCentralGoogle Scholar
  119. 119.
    Hashimoto K, Tsujita M, Miyazaki T, Kitamura K, Yamazaki M, Shin H-S, Watanabe M, Sakimura K, Kano M. Postsynaptic P/Q-type Ca2+ channel in Purkinje cell mediates synaptic competition and elimination in developing cerebellum. Proc Natl Acad Sci U S A. 2011;108(24):9987–92.CrossRefGoogle Scholar
  120. 120.
    Jayabal S, Ljungberg L, Watt AJ. Transient cerebellar alterations during development prior to obvious motor phenotype in a mouse model of spinocerebellar ataxia type 6. J Physiol. 2016;0:1–18.Google Scholar
  121. 121.
    Shakkottai VG, do Carmo Costa M, Dell’Orco JM, Sankaranarayanan A, Wulff H, Paulson HL. Early changes in cerebellar physiology accompany motor dysfunction in the Polyglutamine disease spinocerebellar ataxia type 3. J Neurosci. 2011;31(36):13002–14.PubMedPubMedCentralCrossRefGoogle Scholar
  122. 122.
    Jiao Y, Yan J, Zhao Y, Donahue LR, Beamer WG, Li X, Roe BA, LeDoux MS, Gu W. Carbonic anhydrase-related protein VIII deficiency is associated with a distinctive lifelong gait disorder in waddles mice. Genetics. 2005;171(3):1239–46.PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    White JJ, Arancillo M, King A, Lin T, Miterko LN, Gebre SA, Sillitoe RV. Pathogenesis of severe ataxia and tremor without the typical signs of neurodegeneration. Neurobiol Dis. 2016;86:86–98.PubMedCrossRefGoogle Scholar
  124. 124.
    Hirota J, Ando H, Hamada K, Mikoshiba K. Carbonic anhydrase-related protein is a novel binding protein for inositol 1,4,5-trisphosphate receptor type 1. Biochem J. 2003;372:435–41.PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    Taniuchi K, Nishimori I, Takeuchi T, Ohtsuki Y, Onishi S. cDNA cloning and developmental expression of murine carbonic anhydrase-related proteins VIII, X, and XI. Mol Brain Res. 2002;109(1–2):207–15.PubMedCrossRefGoogle Scholar
  126. 126.
    Kato K. Sequence of a novel carbonic anhydrase-related polypeptide and its exclusive presence in Purkinje cells. FEBS Lett. 1990;271(1–2):137–40.PubMedCrossRefGoogle Scholar
  127. 127.
    Türkmen S, Guo G, Garshasbi M, Hoffmann K, Alshalah AJ, Mischung C, Kuss A, Humphrey N, Mundlos S, Robinson PN. CA8 mutations cause a novel syndrome characterized by ataxia and mild mental retardation with predisposition to quadrupedal gait. PLoS Genet. 2009;5(5):1–8.PubMedPubMedCentralCrossRefGoogle Scholar
  128. 128.
    Hirasawa M, Xu X, Trask RB, Maddatu TP, Johnson BA, Naggert JK, Nishina PM, Ikeda A. Carbonic anhydrase related protein 8 mutation results in aberrant synaptic morphology and excitatory synaptic function in the cerebellum. Mol Cell Neurosci. 2007;35(1):161–70.PubMedCrossRefGoogle Scholar
  129. 129.
    White JJ, Arancillo M, Stay TL, George-Jones NA, Levy SL, Heck DH, Sillitoe RV. Cerebellar zonal patterning relies on Purkinje cell neurotransmission. J Neurosci. 2014;34(24):8231–45.PubMedCrossRefGoogle Scholar
  130. 130.
    Cabeza R, Nyberg L. Imaging cognition II: an empirical review of 275 PET and fMRI studies. J Cogn Neurosci. 2000;12(1):1–47.PubMedCrossRefPubMedCentralGoogle Scholar
  131. 131.
    Schmahmann JD. 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. 2010;20(3):236–60.CrossRefGoogle Scholar
  132. 132.
    Timmann D, Daum I. Cerebellar contributions to cognitive functions: a progress report after two decades of research. Cerebellum. 2007;6:159–62.PubMedCrossRefGoogle Scholar
  133. 133.
    Baumann O, Borra RJ, Bower JM, Cullen KE, Habas C, Ivry RB, Leggio M, Mattingley JB, Molinari M, Moulton EA, Paulin MG, Pavlova MA, Schmahmann JD, Sokolov AA. Consensus paper: The Role of the Cerebellum in Perceptual Processes. Cerebellum. 2014:197–220.CrossRefGoogle Scholar
  134. 134.
    Strick PL, Dum RP, Fiez JA. Cerebellum and nonmotor function. Annu Rev Neurosci. 2009;32:413–34.PubMedCrossRefGoogle Scholar
  135. 135.
    Tavano A, Borgatti R. Evidence for a link among cognition, language and emotion in cerebellar malformations. Cortex. 2010;46(7):907–18.PubMedCrossRefGoogle Scholar
  136. 136.
    Schmahmann J, Sherman J. The cerebellar cognitive affective syndrome. Brain. 1998;121(4):561–79.CrossRefGoogle Scholar
  137. 137.
    Glickstein M. What does the cerebellum really do? Curr Biol. 2007;17(19):824–7.CrossRefGoogle Scholar
  138. 138.
    Lemon R, Edgley S. Life without a cerebellum. Brain. 2010;133(3):652–4.PubMedCrossRefGoogle Scholar
  139. 139.
    Galliano E, Potters J-W, Elgersma Y, Wisden W, Kushner SA, De Zeeuw CI, Hoebeek FE. Synaptic transmission and plasticity at inputs to murine cerebellar Purkinje cells are largely dispensable for standard nonmotor tasks. J Neurosci. 2013;33(31):12599–618.PubMedCrossRefGoogle Scholar
  140. 140.
    Leiner H, Leiner A, Dow R. Does the cerebellum contribute to mental skills? Behav Neurosci. 1986;100(4):443–54.CrossRefGoogle Scholar
  141. 141.
    Bastian AJ. Moving, sensing and learning with cerebellar damage. Curr Opin Neurobiol. 2011;21(4):596–601.PubMedPubMedCentralCrossRefGoogle Scholar
  142. 142.
    D’Angelo E, Casali S. Seeking a unified framework for cerebellar function and dysfunction: from circuit operations to cognition. Front Neural Circuits. 2012;6:116.PubMedPubMedCentralGoogle Scholar
  143. 143.
    Salmi J, Pallesen KJ, Neuvonen T, Brattico E, Korvenoja A, Salonen O, Carlson S. Cognitive and motor loops of the human Cerebrocerebellar system. J Cogn Neurosci. 2010;22(11):2663–76.PubMedCrossRefPubMedCentralGoogle Scholar
  144. 144.
    Stoodley CJ. The cerebellum and neurodevelopmental disorders. Cerebellum. 2016;15(1):34–7.PubMedPubMedCentralCrossRefGoogle Scholar
  145. 145.
    Wang SSH, Kloth AD, Badura A. The cerebellum, sensitive periods, and autism. Neuron. 2014;83(3):518–32.PubMedPubMedCentralCrossRefGoogle Scholar
  146. 146.
    Cantelmi D, Schweizer TA, Cusimano MD. Role of the cerebellum in the neurocognitive sequelae of treatment of tumours of the posterior fossa: an update. Lancet Oncol. 2008;9(6):569–76.PubMedCrossRefGoogle Scholar
  147. 147.
    Fatemi SH, Aldinger KA, Ashwood P, Bauman ML, Blaha CD, Blatt GJ, Chauhan A, Chauhan V, Dager SR, Dickson PE, Estes AM, Goldowitz D, Heck DH, Kemper TL, King BH, Martin LA, Millen KJ, Mittleman G, Mosconi MW, Persico AM, Sweeney JA, Webb SJ, Welsh JP. Consensus paper: Pathological Role of the Cerebellum in Autism. Cerebellum. 2012;11(3):777–807.PubMedCrossRefPubMedCentralGoogle Scholar
  148. 148.
    Becker EBE, Stoodley CJ. Autism spectrum disorder and the cerebellum. 1st, vol. 113. Int Rev Neurobiol. Elsevier Inc.; 2013. 1–34 p.Google Scholar
  149. 149.
    Stoodley CJ, Stein JF. Cerebellar function in developmental dyslexia. Cerebellum. 2013;12(2):267–76.CrossRefGoogle Scholar
  150. 150.
    Nicolson R, Fawcett A, Dean P. Developmental dyslexia: the cerebellar deficit hypothesis. Trends Neurosci. 2001;24(9):508–11.PubMedCrossRefGoogle Scholar
  151. 151.
    Andreasen NC, Pierson R. The role of the cerebellum in schizophrenia. Biol Psychiatry. 2008;64(2):81–8.PubMedPubMedCentralCrossRefGoogle Scholar
  152. 152.
    Mothersill O, Knee-Zaska C, Donohoe G. Emotion and theory of mind in schizophrenia – investigating the role of the cerebellum. Cerebellum. 2016;15(3):357–68.PubMedPubMedCentralCrossRefGoogle Scholar
  153. 153.
    Bauman M, Kemper T. Histoanatomic observations of the brain in early infantile autism. Neurology. 1985;35(6):866–74.PubMedCrossRefGoogle Scholar
  154. 154.
    Kemper T, Bauman M. The contribution of neuropathologic studies to the understanding of autism. Neurol Clin. 1993;11(1):175–87.PubMedCrossRefGoogle Scholar
  155. 155.
    Gharani N, Benayed R, Mancuso V, Brzustowicz LM, Millonig JH. Association of the homeobox transcription factor, ENGRAILED 2, 3, with autism spectrum disorder. Assoc homeobox Transcr factor, ENGRAILED 2, 3, with autism Spectr Disord. Mol Psychiatry. 2004;9(5):474–84.PubMedCrossRefGoogle Scholar
  156. 156.
    Wang L, Jia M, Yue W, Tang F, Qu M, Ruan Y, Lu T, Zhang H, Yan H, Liu J, Guo Y, Zhang J, Yang X, Zhang D. Association of the ENGRAILED 2 (EN2) gene with autism in Chinese Han population. Am J Med Genet Part B Neuropsychiatr Genet. 2008;147(4):434–8.CrossRefGoogle Scholar
  157. 157.
    Sen B, Surindro Singh A, Sinha S, Chatterjee A, Ahmed S, Ghosh S, Usha R. Family-based studies indicate association of Engrailed 2 gene with autism in an Indian population. Genes Brain Behav. 2010;9(2):248–55.CrossRefGoogle Scholar
  158. 158.
    Cheh MA, Millonig JH, Roselli LM, Ming X, Jacobsen E, Kamdar S, Wagner GC. En2 knockout mice display neurobehavioral and neurochemical alterations relevant to autism spectrum disorder. Brain Res. 2006;1116(1):166–176.PubMedCrossRefGoogle Scholar
  159. 159.
    Brielmaier J, Matteson PG, Silverman JL, Senerth JM, Kelly S, Genestine M, Millonig JH, DiCicco-Bloom E, Crawley JN. Autism-relevant social abnormalities and cognitive deficits in engrailed-2 knockout mice. PLoS One. 2012;7(7):40–2.PubMedPubMedCentralCrossRefGoogle Scholar
  160. 160.
    Bürk K, Bösch S, Globas C, Zühlke C, Daum I, Klockgether T, Dichgans J. Executive dysfunction in spinocerebellar ataxia type 1. Eur Neurol. 2001;46(1):43–8.PubMedCrossRefGoogle Scholar
  161. 161.
    Tsai PT, Hull C, Chu YX, Greene-Colozzi E, Sadowski AR, Leech JM, Steinberg J, Crawley JN, Regehr WG, Sahin M. Autistic-like behaviour and cerebellar dysfunction in Purkinje cell Tsc1 mutant mice. Nature. 2012;488(7413):647-651.PubMedPubMedCentralCrossRefGoogle Scholar
  162. 162.
    Ito M. Control of mental activities by internal models in the cerebellum. Nature Reviews Neuroscience. 2008;9(4):304–13.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Department of Pathology & ImmunologyBaylor College of MedicineHoustonUSA
  2. 2.Department of NeuroscienceBaylor College of MedicineHoustonUSA
  3. 3.The Jan and Dan Duncan Neurological Research Institute at Texas Children’s HospitalHoustonUSA
  4. 4.Program in Developmental BiologyBaylor College of MedicineHoustonUSA

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