Molecular Neurobiology

, Volume 55, Issue 5, pp 3901–3915 | Cite as

Neonatal Hyperoxia Perturbs Neuronal Development in the Cerebellum

  • Till Scheuer
  • Yuliya Sharkovska
  • Victor Tarabykin
  • Katharina Marggraf
  • Vivien Brockmöller
  • Christoph Bührer
  • Stefanie Endesfelder
  • Thomas Schmitz


Impaired postnatal brain development of preterm infants often results in neurological deficits. Besides pathologies of the forebrain, maldeveolopment of the cerebellum is increasingly recognized to contribute to psychomotor impairments of many former preterm infants. However, causes are poorly defined. We used a hyperoxia model to define neonatal damage in cerebellar granule cell precursors (GCPs) and in Purkinje cells (PCs) known to be essential for interaction with GCPs during development. We exposed newborn rats to 24 h 80% O2 from age P6 to P7 to identify postnatal and long-term damage in cerebellar GCPs at age P7 after hyperoxia and also after recovery in room air thereafter until P11 and P30. We determined proliferation and apoptosis of GCPs and immature neurons by immunohistochemistry, quantified neuronal damage by qPCR and Western blots for neuronal markers, and measured dendrite outgrowth of PCs by CALB1 immunostainings and by Sholl analysis of Golgi stainings. After hyperoxia, proliferation of PAX6+ GCPs was decreased at P7, while DCX + CASP3+ cells were increased at P11. Neuronal markers Pax6, Tbr2, and Prox1 were downregulated at P11 and P30. Neuronal damage was confirmed by reduced NeuN protein expression at P30. Sonic hedgehog (SHH) was significantly decreased at P7 and P11 after hyperoxia and coincided with lower CyclinD2 and Hes1 expression at P7. The granule cell injury was accompanied by hampered PC maturation with delayed dendrite formation and impaired branching. Neonatal injury induced by hyperoxia inhibits PC functioning and impairs granule cell development. As a conclusion, maldevelopment of the cerebellar neurons found in preterm infants could be caused by postnatal oxygen toxicity.


Cerebellum Granule cells Hyperoxia Preterm infants Purkinje cells Sonic hedgehog 



We thank Mrs. Evelyn Strauss and Mrs. Ruth Herrmann for help with paraffin sections and with Western blots.

Compliance with Ethical Standards

All animal experiments were performed in accordance with international guidelines for good laboratory practice and were approved by the animal welfare committees of Berlin, Germany.

Conflict of Interest

The authors declare that they have no conflict of interest.


This work was supported by Deutsche Forschungsgemeinschaft (SCHM3007/2-1, SCHM3007/3-2) (Thomas Schmitz and Till Scheuer), (TA 303/6-1) (Victor Tarabykin), Sonnenfeld Stiftung (Till Scheuer), and the Helga und Alfred Buchwald-Stiftung (Till Scheuer).

Supplementary material

12035_2017_612_Fig9_ESM.gif (268 kb)
Supplemental figure 1

Hyperoxia did not perturb GC migration. To confirm no influence of hyperoxia on GC migration we performed immunohistochemical stainings of 10 μm sagittal cerebellar sections for PAX6 at the ages P7, P11 and P15 (A). We analyzed the peripheral part of the same lobes in each animal. At all developmental time points the thickness of the PAX6+ EGL was similar in control and hyperoxia experienced rats (B) (n = 4). Gene expression of Sdf1 at P7 and P11 was not affected by hyperoxia (C) (P7 n = 8, P11 n = 6). Scale bar = 50 μm (GIF 267 kb)

12035_2017_612_MOESM1_ESM.tif (74 mb)
High Resolution Image (TIFF 75815 kb)


  1. 1.
    Brossard-Racine M, du Plessis AJ, Limperopoulos C (2015) Developmental cerebellar cognitive affective syndrome in ex-preterm survivors following cerebellar injury. Cerebellum 14:151–164. doi: 10.1007/s12311-014-0597-9 CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    de Kieviet JF, Piek JP, Aarnoudse-Moens CS, Oosterlaan J (2009) Motor development in very preterm and very low-birth-weight children from birth to adolescence: a meta-analysis. JAMA 302:2235–2242. doi: 10.1001/jama.2009.1708 CrossRefPubMedGoogle Scholar
  3. 3.
    Volpe JJ (2009) Brain injury in premature infants: A complex amalgam of destructive and developmental disturbances. Lancet Neurol 8:110–124. doi: 10.1016/S1474-4422(08)70294-1 CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    van Tilborg E, Heijnen CJ, Benders MJ et al (2016) Impaired oligodendrocyte maturation in preterm infants: Potential therapeutic targets. Prog Neurobiol 136:28–49. doi: 10.1016/j.pneurobio.2015.11.002 CrossRefPubMedGoogle Scholar
  5. 5.
    Rose J, Cahill-Rowley K, Vassar R et al (2015) Neonatal brain microstructure correlates of neurodevelopment and gait in preterm children 18-22 mo of age: an MRI and DTI study. Pediatr Res 78:700–708. doi: 10.1038/pr.2015.157 CrossRefPubMedGoogle Scholar
  6. 6.
    Volpe JJ (2009) Cerebellum of the premature infant: rapidly developing, vulnerable, clinically important. J Child Neurol 24:1085–1104. doi: 10.1177/0883073809338067 CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Riva D, 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):1051–1061CrossRefPubMedGoogle Scholar
  8. 8.
    Stoodley CJ, Valera EM, Schmahmann JD (2012) Functional topography of the cerebellum for motor and cognitive tasks: an fMRI study. NeuroImage 59:1560–1570. doi: 10.1016/j.neuroimage.2011.08.065 CrossRefPubMedGoogle Scholar
  9. 9.
    Wang SS-H, Kloth AD, Badura A (2014) The cerebellum, sensitive periods, and autism. Neuron 83:518–532. doi: 10.1016/j.neuron.2014.07.016 CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Fleming JT, He W, Hao C et al (2013) The Purkinje neuron acts as a central regulator of spatially and functionally distinct cerebellar precursors. Dev Cell 27:278–292. doi: 10.1016/j.devcel.2013.10.008 CrossRefPubMedGoogle Scholar
  11. 11.
    Haldipur P, Bharti U, Alberti C et al (2011) Preterm delivery disrupts the developmental program of the cerebellum. PLoS One 6:e23449. doi: 10.1371/journal.pone.0023449 CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Tam EWY (2013) Potential mechanisms of cerebellar hypoplasia in prematurity. Neuroradiology 55(Suppl 2):41–46. doi: 10.1007/s00234-013-1230-1 CrossRefPubMedGoogle Scholar
  13. 13.
    Baud O, Gressens P (2011) Hedgehog rushes to the rescue of the developing cerebellum. Sci Transl Med 3:105ps40. doi: 10.1126/scitranslmed.3003080 CrossRefPubMedGoogle Scholar
  14. 14.
    Lee EY, Ji H, Ouyang Z et al (2010) Hedgehog pathway-regulated gene networks in cerebellum development and tumorigenesis. Proc Natl Acad Sci U S A 107:9736–9741. doi: 10.1073/pnas.1004602107 CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Wechsler-Reya RJ, Scott MP (1999) Control of neuronal precursor proliferation in the cerebellum by sonic hedgehog. Neuron 22:103–114CrossRefPubMedGoogle Scholar
  16. 16.
    Butts T, Chaplin N, Wingate RJT (2011) Can clues from evolution unlock the molecular development of the cerebellum? Mol Neurobiol 43:67–76. doi: 10.1007/s12035-010-8160-2 CrossRefPubMedGoogle Scholar
  17. 17.
    Chang JC, Leung M, Gokozan HN et al (2015) Mitotic events in cerebellar granule progenitor cells that expand cerebellar surface area are critical for normal cerebellar cortical lamination in mice. J Neuropathol Exp Neurol 74:261–272. doi: 10.1097/NEN.0000000000000171 CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Goldowitz D, Hamre K (1998) The cells and molecules that make a cerebellum. Trends Neurosci 21:375–382CrossRefPubMedGoogle Scholar
  19. 19.
    White JJ, Sillitoe RV (2013) Development of the cerebellum: from gene expression patterns to circuit maps. Wiley Interdiscip Rev Dev Biol 2:149–164. doi: 10.1002/wdev.65 CrossRefPubMedGoogle Scholar
  20. 20.
    D’Angelo E, Mazzarello P, Prestori F et al (2011) The cerebellar network: from structure to function and dynamics. Brain Res Rev 66:5–15. doi: 10.1016/j.brainresrev.2010.10.002 CrossRefPubMedGoogle Scholar
  21. 21.
    Herculano-Houzel S (2010) Coordinated scaling of cortical and cerebellar numbers of neurons. Front Neuroanat 4:12. doi: 10.3389/fnana.2010.00012 PubMedPubMedCentralGoogle Scholar
  22. 22.
    Rössert C, Dean P, Porrill J (2015) At the edge of chaos: how cerebellar granular layer network dynamics can provide the basis for temporal filters. PLoS Comput Biol 11:e1004515. doi: 10.1371/journal.pcbi.1004515 CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Dammann O, Leviton A (2004) Inflammatory brain damage in preterm newborns--dry numbers, wet lab, and causal inferences. Early Hum Dev 79:1–15. doi: 10.1016/j.earlhumdev.2004.04.009 CrossRefPubMedGoogle Scholar
  24. 24.
    Kinney HC (2005) Human myelination and perinatal white matter disorders. J Neurol Sci 228:190–192. doi: 10.1016/j.jns.2004.10.006 CrossRefPubMedGoogle Scholar
  25. 25.
    Glass HC, Glidden D, Jeremy RJ et al (2009) Clinical neonatal seizures are independently associated with outcome in infants at risk for hypoxic-ischemic brain injury. J Pediatr 155:318–323. doi: 10.1016/j.jpeds.2009.03.040 CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Hagberg H, David Edwards A, Groenendaal F (2015) Perinatal brain damage: The term infant. Neurobiol Dis. doi: 10.1016/j.nbd.2015.09.011
  27. 27.
    Ronen GM, Penney S, Andrews W (1999) The epidemiology of clinical neonatal seizures in Newfoundland: a population-based study. J Pediatr 134:71–75CrossRefPubMedGoogle Scholar
  28. 28.
    Deulofeut R, Dudell G, Sola A (2007) Treatment-by-gender effect when aiming to avoid hyperoxia in preterm infants in the NICU. Acta Paediatr 96:990–994. doi: 10.1111/j.1651-2227.2007.00365.x CrossRefPubMedGoogle Scholar
  29. 29.
    Endesfelder S, Zaak I, Weichelt U et al (2013) Caffeine protects neuronal cells against injury caused by hyperoxia in the immature brain. Free Radic Biol Med 67C:221–234. doi: 10.1016/j.freeradbiomed.2013.09.026 Google Scholar
  30. 30.
    Castillo A, Sola A, Baquero H et al (2008) Pulse oxygen saturation levels and arterial oxygen tension values in newborns receiving oxygen therapy in the neonatal intensive care unit: is 85% to 93% an acceptable range? Pediatrics 121:882–889. doi: 10.1542/peds.2007-0117 CrossRefPubMedGoogle Scholar
  31. 31.
    Schmitz T, Ritter J, Mueller S et al (2011) Cellular changes underlying hyperoxia-induced delay of white matter development. J Neurosci 31:4327–4344. doi: 10.1523/JNEUROSCI.3942-10.2011 CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Sifringer M, von Haefen C, Krain M et al (2015) Neuroprotective effect of dexmedetomidine on hyperoxia-induced toxicity in the neonatal rat brain. Oxidative Med Cell Longev 2015:530371. doi: 10.1155/2015/530371 CrossRefGoogle Scholar
  33. 33.
    Scheuer T, Brockmöller V, Blanco Knowlton M et al (2015) Oligodendroglial maldevelopment in the cerebellum after postnatal hyperoxia and its prevention by minocycline. Glia 63:1825–1839. doi: 10.1002/glia.22847 CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Andrews K, Fitzgerald M (1997) Biological barriers to paediatric pain management. Clin J Pain 13:138–143CrossRefPubMedGoogle Scholar
  35. 35.
    Ikonomidou C, Kaindl AM (2011) Neuronal death and oxidative stress in the developing brain. Antioxid Redox Signal 14:1535–1550. doi: 10.1089/ars.2010.3581 CrossRefPubMedGoogle Scholar
  36. 36.
    Schmitz T, Krabbe G, Weikert G et al (2014) Minocycline protects the immature white matter against hyperoxia. Exp Neurol 254:153–165. doi: 10.1016/j.expneurol.2014.01.017 CrossRefPubMedGoogle Scholar
  37. 37.
    Felderhoff-Mueser U, Bittigau P, Sifringer M et al (2004) Oxygen causes cell death in the developing brain. Neurobiol Dis 17:273–282. doi: 10.1016/j.nbd.2004.07.019 CrossRefPubMedGoogle Scholar
  38. 38.
    Zaqout S, Kaindl AM (2016) Golgi-cox staining step by step. Front Neuroanat 10:38. doi: 10.3389/fnana.2016.00038 CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Rosário M, Schuster S, Jüttner R et al (2012) Neocortical dendritic complexity is controlled during development by NOMA-GAP-dependent inhibition of Cdc42 and activation of cofilin. Genes Dev 26:1743–1757. doi: 10.1101/gad.191593.112 CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Sholl DA (1953) Dendritic organization in the neurons of the visual and motor cortices of the cat. J Anat 87:387–406PubMedPubMedCentralGoogle Scholar
  41. 41.
    Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods 25:402–408. doi: 10.1006/meth.2001.1262 CrossRefPubMedGoogle Scholar
  42. 42.
    Contestabile A (2002) Cerebellar granule cells as a model to study mechanisms of neuronal apoptosis or survival in vivo and in vitro. Cerebellum 1:41–55. doi: 10.1080/147342202753203087 CrossRefPubMedGoogle Scholar
  43. 43.
    Hevner RF, Hodge RD, Daza RAM, Englund C (2006) Transcription factors in glutamatergic neurogenesis: conserved programs in neocortex, cerebellum, and adult hippocampus. Neurosci Res 55:223–233. doi: 10.1016/j.neures.2006.03.004 CrossRefPubMedGoogle Scholar
  44. 44.
    Weyer A, Schilling K (2003) Developmental and cell type-specific expression of the neuronal marker NeuN in the murine cerebellum. J Neurosci Res 73:400–409. doi: 10.1002/jnr.10655 CrossRefPubMedGoogle Scholar
  45. 45.
    Galeeva A, Treuter E, Tomarev S, Pelto-Huikko M (2007) A prospero-related homeobox gene Prox-1 is expressed during postnatal brain development as well as in the adult rodent brain. Neuroscience 146:604–616. doi: 10.1016/j.neuroscience.2007.02.002 CrossRefPubMedGoogle Scholar
  46. 46.
    Vaillant C, Monard D (2009) SHH pathway and cerebellar development. Cerebellum 8:291–301. doi: 10.1007/s12311-009-0094-8 CrossRefPubMedGoogle Scholar
  47. 47.
    Solecki DJ, Liu XL, Tomoda T et al (2001) Activated Notch2 signaling inhibits differentiation of cerebellar granule neuron precursors by maintaining proliferation. Neuron 31:557–568CrossRefPubMedGoogle Scholar
  48. 48.
    Fogarty MP, Emmenegger BA, Grasfeder LL et al (2007) Fibroblast growth factor blocks sonic hedgehog signaling in neuronal precursors and tumor cells. Proc Natl Acad Sci U S A 104:2973–2978. doi: 10.1073/pnas.0605770104 CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Yu T, Yaguchi Y, Echevarria D et al (2011) Sprouty genes prevent excessive FGF signalling in multiple cell types throughout development of the cerebellum. Development 138:2957–2968. doi: 10.1242/dev.063784 CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Harvey RJ, Napper RM (1988) Quantitative study of granule and Purkinje cells in the cerebellar cortex of the rat. J Comp Neurol 274:151–157. doi: 10.1002/cne.902740202 CrossRefPubMedGoogle Scholar
  51. 51.
    Sillitoe RV, Joyner AL (2007) Morphology, molecular codes, and circuitry produce the three-dimensional complexity of the cerebellum. Annu Rev Cell Dev Biol 23:549–577. doi: 10.1146/annurev.cellbio.23.090506.123237 CrossRefPubMedGoogle Scholar
  52. 52.
    Mizuhara E, Minaki Y, Nakatani T et al (2010) Purkinje cells originate from cerebellar ventricular zone progenitors positive for Neph3 and E-cadherin. Dev Biol 338:202–214. doi: 10.1016/j.ydbio.2009.11.032 CrossRefPubMedGoogle Scholar
  53. 53.
    Isope P, Barbour B (2002) Properties of unitary granule cell-->Purkinje cell synapses in adult rat cerebellar slices. J Neurosci 22:9668–9678PubMedGoogle Scholar
  54. 54.
    Kaneko M, Yamaguchi K, Eiraku M et al (2011) Remodeling of monoplanar Purkinje cell dendrites during cerebellar circuit formation. PLoS One 6:e20108. doi: 10.1371/journal.pone.0020108 CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    McKay BE, Turner RW (2005) Physiological and morphological development of the rat cerebellar Purkinje cell. J Physiol Lond 567:829–850. doi: 10.1113/jphysiol.2005.089383 CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Kapfhammer JP (2004) Cellular and molecular control of dendritic growth and development of cerebellar Purkinje cells. Prog Histochem Cytochem 39:131–182CrossRefPubMedGoogle Scholar
  57. 57.
    Metzger F (2010) Molecular and cellular control of dendrite maturation during brain development. Curr Mol Pharmacol 3:1–11CrossRefPubMedGoogle Scholar
  58. 58.
    Borghesani PR, Peyrin JM, Klein R et al (2002) BDNF stimulates migration of cerebellar granule cells. Development 129:1435–1442PubMedGoogle Scholar
  59. 59.
    Limperopoulos C, Soul JS, Gauvreau K et al (2005) Late gestation cerebellar growth is rapid and impeded by premature birth. Pediatrics 115:688–695. doi: 10.1542/peds.2004-1169 CrossRefPubMedGoogle Scholar
  60. 60.
    Limperopoulos C, Chilingaryan G, Guizard N et al (2010) Cerebellar injury in the premature infant is associated with impaired growth of specific cerebral regions. Pediatr Res 68:145–150. doi: 10.1203/PDR.0b013e3181e1d032 CrossRefPubMedGoogle Scholar
  61. 61.
    Rudolph CD (2003) Rudolph’s pediatrics, 21st ed. McGraw-Hill, Medical Pub. Division, New YorkGoogle Scholar
  62. 62.
    Gerstner B, Sifringer M, Dzietko M et al (2007) Estradiol attenuates hyperoxia-induced cell death in the developing white matter. Ann Neurol 61:562–573. doi: 10.1002/ana.21118 CrossRefPubMedGoogle Scholar
  63. 63.
    Kenney AM, Rowitch DH (2000) Sonic hedgehog promotes G(1) cyclin expression and sustained cell cycle progression in mammalian neuronal precursors. Mol Cell Biol 20:9055–9067CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Morales AV, Espeso-Gil S, Ocaña I et al (2016) FGF signaling enhances a sonic hedgehog negative feedback loop at the initiation of spinal cord ventral patterning. Dev Neurobiol 76:956–971. doi: 10.1002/dneu.22368 CrossRefPubMedGoogle Scholar
  65. 65.
    Alzheimer C, Werner S (2002) Fibroblast growth factors and neuroprotection. Adv Exp Med Biol 513:335–351CrossRefPubMedGoogle Scholar
  66. 66.
    Timmer M, Cesnulevicius K, Winkler C et al (2007) Fibroblast growth factor (FGF)-2 and FGF receptor 3 are required for the development of the substantia nigra, and FGF-2 plays a crucial role for the rescue of dopaminergic neurons after 6-hydroxydopamine lesion. J Neurosci 27:459–471. doi: 10.1523/JNEUROSCI.4493-06.2007 CrossRefPubMedGoogle Scholar
  67. 67.
    Almeida RD, Manadas BJ, Melo CV et al (2005) Neuroprotection by BDNF against glutamate-induced apoptotic cell death is mediated by ERK and PI3-kinase pathways. Cell Death Differ 12:1329–1343. doi: 10.1038/sj.cdd.4401662 CrossRefPubMedGoogle Scholar
  68. 68.
    Van Kanegan MJ, He DN, Dunn DE et al (2014) BDNF mediates neuroprotection against oxygen-glucose deprivation by the cardiac glycoside oleandrin. J Neurosci 34:963–968. doi: 10.1523/JNEUROSCI.2700-13.2014 CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Zhang Y, Pardridge WM (2001) Neuroprotection in transient focal brain ischemia after delayed intravenous administration of brain-derived neurotrophic factor conjugated to a blood-brain barrier drug targeting system. Stroke 32:1378–1384CrossRefPubMedGoogle Scholar
  70. 70.
    Fagel DM, Ganat Y, Silbereis J et al (2006) Cortical neurogenesis enhanced by chronic perinatal hypoxia. Exp Neurol 199:77–91. doi: 10.1016/j.expneurol.2005.04.006 CrossRefPubMedGoogle Scholar
  71. 71.
    Gage FH (2000) Mammalian neural stem cells. Science 287:1433–1438CrossRefPubMedGoogle Scholar
  72. 72.
    Gould E (2007) How widespread is adult neurogenesis in mammals? Nat Rev Neurosci 8:481–488. doi: 10.1038/nrn2147 CrossRefPubMedGoogle Scholar
  73. 73.
    Chung S-H, Kim C-T, Jeong Y-G, Lee N-S (2010) TBR2-immunopsitive unipolar brush cells are associated with ectopic zebrin II-immunoreactive Purkinje cell clusters in the cerebellum of scrambler mice. Anat Cell Biol 43:72–77. doi: 10.5115/acb.2010.43.1.72 CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    McDole B, Isgor C, Pare C, Guthrie K (2015) BDNF over-expression increases olfactory bulb granule cell dendritic spine density in vivo. Neuroscience 304:146–160. doi: 10.1016/j.neuroscience.2015.07.056 CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Haraguchi S, Sasahara K, Shikimi H et al (2012) Estradiol promotes purkinje dendritic growth, spinogenesis, and synaptogenesis during neonatal life by inducing the expression of BDNF. Cerebellum 11:416–417. doi: 10.1007/s12311-011-0342-6 CrossRefPubMedGoogle Scholar
  76. 76.
    Baptista CA, Hatten ME, Blazeski R, Mason CA (1994) Cell-cell interactions influence survival and differentiation of purified Purkinje cells in vitro. Neuron 12:243–260CrossRefPubMedGoogle Scholar
  77. 77.
    Morrison ME, Mason CA (1998) Granule neuron regulation of Purkinje cell development: striking a balance between neurotrophin and glutamate signaling. J Neurosci 18:3563–3573CrossRefPubMedGoogle Scholar
  78. 78.
    Hirai H, Launey T (2000) The regulatory connection between the activity of granule cell NMDA receptors and dendritic differentiation of cerebellar Purkinje cells. J Neurosci 20:5217–5224PubMedGoogle Scholar
  79. 79.
    Bouslama-Oueghlani L, Wehrlé R, Doulazmi M et al (2012) Purkinje cell maturation participates in the control of oligodendrocyte differentiation: role of sonic hedgehog and vitronectin. PLoS One 7:e49015. doi: 10.1371/journal.pone.0049015 CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    Collin L, Doretto S, Malerba M et al (2007) Oligodendrocyte ablation affects the coordinated interaction between granule and Purkinje neurons during cerebellum development. Exp Cell Res 313:2946–2957. doi: 10.1016/j.yexcr.2007.05.003 CrossRefPubMedGoogle Scholar
  81. 81.
    Mathis C, Collin L, Borrelli E (2003) Oligodendrocyte ablation impairs cerebellum development. Development 130:4709–4718. doi: 10.1242/dev.00675 CrossRefPubMedGoogle Scholar
  82. 82.
    Bellamy TC (2006) Interactions between Purkinje neurones and Bergmann glia. Cerebellum 5:116–126. doi: 10.1080/14734220600724569 CrossRefPubMedGoogle Scholar
  83. 83.
    Shaham S (2005) Glia-neuron interactions in nervous system function and development. Curr Top Dev Biol 69:39–66. doi: 10.1016/S0070-2153(05)69003-5 CrossRefPubMedGoogle Scholar
  84. 84.
    Klein JA, Ackerman SL (2003) Oxidative stress, cell cycle, and neurodegeneration. J Clin Invest 111:785–793. doi: 10.1172/JCI18182 CrossRefPubMedPubMedCentralGoogle Scholar
  85. 85.
    Konyalioglu S, Armagan G, Yalcin A et al (2013) Effects of resveratrol on hydrogen peroxide-induced oxidative stress in embryonic neural stem cells. Neural Regen Res 8:485–495. doi: 10.3969/j.issn.1673-5374.2013.06.001 PubMedPubMedCentralGoogle Scholar
  86. 86.
    De Luca A, Parmigiani E, Tosatto G et al (2015) Exogenous sonic hedgehog modulates the pool of GABAergic interneurons during cerebellar development. Cerebellum 14:72–85. doi: 10.1007/s12311-014-0596-x CrossRefPubMedGoogle Scholar
  87. 87.
    Dahmane N, Ruiz i Altaba A (1999) Sonic hedgehog regulates the growth and patterning of the cerebellum. Development 126:3089–3100PubMedGoogle Scholar
  88. 88.
    Steinlin M (2008) Cerebellar disorders in childhood: Cognitive problems. Cerebellum 7:607–610. doi: 10.1007/s12311-008-0083-3 CrossRefPubMedGoogle Scholar
  89. 89.
    Kim H, Gano D, Ho M-L et al (2016) Hindbrain regional growth in preterm newborns and its impairment in relation to brain injury. Hum Brain Mapp 37:678–688. doi: 10.1002/hbm.23058 CrossRefPubMedGoogle Scholar
  90. 90.
    Steggerda SJ, Leijser LM, Wiggers-de Bruïne FT et al (2009) Cerebellar injury in preterm infants: incidence and findings on US and MR images. Radiology 252:190–199. doi: 10.1148/radiol.2521081525 CrossRefPubMedGoogle Scholar
  91. 91.
    Abbott A (2015) Neuroscience: The brain, interrupted. Nature 518:24–26. doi: 10.1038/518024a CrossRefPubMedGoogle Scholar
  92. 92.
    Khwaja O, Volpe JJ (2008) Pathogenesis of cerebral white matter injury of prematurity. Arch Dis Child Fetal Neonatal Ed 93:F153–F161. doi: 10.1136/adc.2006.108837 CrossRefPubMedPubMedCentralGoogle Scholar
  93. 93.
    Georgeson GD, Szony BJ, Streitman K et al (2002) Antioxidant enzyme activities are decreased in preterm infants and in neonates born via caesarean section. Eur J Obstet Gynecol Reprod Biol 103:136–139CrossRefPubMedGoogle Scholar

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© Springer Science+Business Media New York 2017

Authors and Affiliations

  1. 1.Department for NeonatologyCharité University Medical CenterBerlinGermany
  2. 2.Institute of BioanalyticsTechnische Universität BerlinBerlinGermany
  3. 3.Klinik für NeonatologieCharité Universitätsmedizin BerlinBerlinGermany
  4. 4.Institute for Cell and Neurobiology, Center for AnatomyCharité University Medical CenterBerlinGermany

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