Skip to main content

Advertisement

SpringerLink
Log in

Injury of the Developing Cerebellum: A Brief Review of the Effects of Endotoxin and Asphyxial Challenges in the Late Gestation Sheep Fetus

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

Abstract

The vulnerability of the fetal and newborn brain to events in utero or at birth that cause damage arising from perturbations of cerebral blood flow and metabolism, such as the accumulation of free radicals and excitatory transmitters to neurotoxic levels, has received considerable attention over the last few decades. Attention has usually been on the damage to cerebral structures, particularly, periventricular white matter. The rapid growth of the cerebellum in the latter half of fetal life in species with long gestations, such as the human and sheep, suggests that this may be a particularly important time for the development of cerebellar structure and function. In this short review, we summarize data from recent studies with fetal sheep showing that the developing cerebellum is particularly sensitive to infectious processes, chronic hypoxia and asphyxia. The data demonstrates that the cerebellum should be further studied in insults of this nature as it responds differently to the remainder of the brain. Damage to this region of the brain has implications not only for the development of motor control and posture, but also for higher cognitive processes and the subsequent development of complex behaviours, such as learning, memory and attention.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Allen G, Courchesne E. The cerebellum and non-motor function: clinical implications. Mol Psychiatry. 1998;3(3):207–10.

    Article  CAS  PubMed  Google Scholar 

  2. Allen G, Muller RA, Courchesne E. Cerebellar function in autism: functional magnetic resonance image activation during a simple motor task. Biol Psychiatry. 2004;56(4):269–78.

    Article  PubMed  Google Scholar 

  3. Sarna JR, Hawkes R. Patterned Purkinje cell death in the cerebellum. Prog Neurobiol. 2003;70(6):473–507.

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  5. Levisohn L, Cronin-Golomb A, Schmahmann JD. Neuropsychological consequences of cerebellar tumour resection in children: cerebellar cognitive affective syndrome in a paediatric population. Brain. 2000;123(Pt 5):1041–50.

    Article  PubMed  Google Scholar 

  6. Kemper TL, Bauman M. Neuropathology of infantile autism. J Neuropathol Exp Neurol. 1998;57(7):645–52.

    Article  CAS  PubMed  Google Scholar 

  7. Kern JK. Purkinje cell vulnerability and autism: a possible etiological connection. Brain Dev. 2003;25(6):377–82.

    Article  PubMed  Google Scholar 

  8. Abraham H, Tornoczky T, Kosztolanyi G, Seress L. Cell formation in the cortical layers of the developing human cerebellum. Int J Dev Neurosci. 2001;19(1):53–62.

    Article  CAS  PubMed  Google Scholar 

  9. Rakic P, Sidman RL. Histogenesis of cortical layers in human cerebellum, particularly the lamina dissecans. J Comp Neurol. 1970;139(4):473–500.

    Article  CAS  PubMed  Google Scholar 

  10. Bodensteiner JB, Johnsen SD. Cerebellar injury in the extremely premature infant: newly recognized but relatively common outcome. J Child Neurol. 2005;20(2):139–42.

    Article  PubMed  Google Scholar 

  11. Limperopoulos C, Soul JS, Haidar H, Huppi PS, Bassan H, Warfield SK, et al. Impaired trophic interactions between the cerebellum and the cerebrum among preterm infants. Pediatrics. 2005;116(4):844–50.

    Article  PubMed  Google Scholar 

  12. Limperopoulos C, Soul JS, Gauvreau K, Huppi PS, Warfield SK, Bassan H, et al. Late gestation cerebellar growth is rapid and impeded by premature birth. Pediatrics. 2005;115(3):688–95.

    Article  PubMed  Google Scholar 

  13. Johnsen SD, Bodensteiner JB, Lotze TE. Frequency and nature of cerebellar injury in the extremely premature survivor with cerebral palsy. J Child Neurol. 2005;20(1):60–4.

    Article  PubMed  Google Scholar 

  14. Mercuri E, He J, Curati WL, Dubowitz LM, Cowan FM, Bydder GM. Cerebellar infarction and atrophy in infants and children with a history of premature birth. Pediatr Radiol. 1997;27(2):139–43.

    Article  CAS  PubMed  Google Scholar 

  15. Le Strange E, Saeed N, Cowan FM, Edwards AD, Rutherford MA. MR imaging quantification of cerebellar growth following hypoxic-ischemic injury to the neonatal brain. AJNR Am J Neuroradiol. 2004;25(3):463–8.

    PubMed  Google Scholar 

  16. Golja AM, Estroff JA, Robertson RL. Fetal imaging of central nervous system abnormalities. Neuroimaging Clin N Am. 2004;14(2):293–306. viii.

    Article  PubMed  Google Scholar 

  17. Limperopoulos C, Robertson RL, Estroff JA, Barnewolt C, Levine D, Bassan H, et al. Diagnosis of inferior vermian hypoplasia by fetal magnetic resonance imaging: potential pitfalls and neurodevelopmental outcome. Am J Obstet Gynecol. 2006;194(4):1070–6.

    Article  PubMed Central  PubMed  Google Scholar 

  18. Rees S, Harding R. The effects of intrauterine growth retardation on the development of the Purkinje cell dendritic tree in the cerebellar cortex of fetal sheep: a note on the ontogeny of the Purkinje cell. Int J Dev Neurosci. 1988;6(5):461–9.

    Article  CAS  PubMed  Google Scholar 

  19. Inage YW, Itoh M, Wada K, Takashima S. Expression of two glutamate transporters, GLAST and EAAT4, in the human cerebellum: their correlation in development and neonatal hypoxic-ischemic damage. J Neuropathol Exp Neurol. 1998;57(6):554–62.

    Article  CAS  PubMed  Google Scholar 

  20. Rees S, Stringer M, Just Y, Hooper SB, Harding R. The vulnerability of the fetal sheep brain to hypoxemia at mid-gestation. Brain Res Dev Brain Res. 1997;103(2):103–18.

    Article  CAS  PubMed  Google Scholar 

  21. Castillo-Melendez M, Chow JA, Walker DW. Lipid peroxidation, caspase-3 immunoreactivity, and pyknosis in late-gestation fetal sheep brain after umbilical cord occlusion. Pediatr Res. 2004;55(5):864–71.

    Article  CAS  PubMed  Google Scholar 

  22. Didenko VV, Ngo H, Minchew CL, Boudreaux DJ, Widmayer MA, Baskin DS. Caspase-3-dependent and -independent apoptosis in focal brain ischemia. Mol Med. 2002;8(7):347–52.

    CAS  PubMed Central  PubMed  Google Scholar 

  23. Dell'Anna E, Chen Y, Engidawork E, Andersson K, Lubec G, Luthman J, et al. Delayed neuronal death following perinatal asphyxia in rat. Exp Brain Res. 1997;115(1):105–15.

    Article  PubMed  Google Scholar 

  24. Kohlhauser C, Mosgoller W, Hoger H, Lubec B. Myelination deficits in brain of rats following perinatal asphyxia. Life Sci. 2000;67(19):2355–68.

    Article  CAS  PubMed  Google Scholar 

  25. Lee C, Kim DW, Jeon GS, Roh EJ, Seo JH, Wang KC, et al. Cerebellar alterations induced by chronic hypoxia: an immunohistochemical study using a chick embryonic model. Brain Res. 2001;901(1–2):271–6.

    Article  CAS  PubMed  Google Scholar 

  26. Lafarga M, Berciano MT, Blanco M. Ectopic Purkinje cells in the cerebellar white matter of normal adult rodents: a Golgi study. Acta Anat (Basel). 1986;127(1):53–8.

    Article  CAS  Google Scholar 

  27. Mallard EC, Rees S, Stringer M, Cock ML, Harding R. Effects of chronic placental insufficiency on brain development in fetal sheep. Pediatr Res. 1998;43(2):262–70.

    Article  CAS  PubMed  Google Scholar 

  28. Storm JE, Valdes JJ, Fechter LD. Postnatal alterations in cerebellar GABA content, GABA uptake and morphology following exposure to carbon monoxide early in development. Dev Neurosci. 1986;8(4):251–61.

    Article  CAS  PubMed  Google Scholar 

  29. Iino M, Goto K, Kakegawa W, Okado H, Sudo M, Ishiuchi S, et al. Glia-synapse interaction through Ca2+−permeable AMPA receptors in Bergmann glia. Science. 2001;292(5518):926–9.

    Article  CAS  PubMed  Google Scholar 

  30. Seil FJ. Interactions between cerebellar Purkinje cells and their associated astrocytes. Histol Histopathol. 2001;16(3):955–68.

    CAS  PubMed  Google Scholar 

  31. Murai KK, Nguyen LN, Irie F, Yamaguchi Y, Pasquale EB. Control of hippocampal dendritic spine morphology through ephrin-A3/EphA4 signaling. Nat Neurosci. 2003;6(2):153–60.

    Article  CAS  PubMed  Google Scholar 

  32. Ramon Y Cajal, S, Histologie du systeme nerveux de l'homme et des vertebras. Paris, Maloine. Reprinted by Consejo Superior de Investigaciones Cientificas, Madrid, 1955. 1911

  33. Tanaka M, Maeda N, Noda M, Marunouchi T. A chondroitin sulfate proteoglycan PTPzeta /RPTPbeta regulates the morphogenesis of Purkinje cell dendrites in the developing cerebellum. J Neurosci. 2003;23(7):2804–14.

    CAS  PubMed  Google Scholar 

  34. Yamada K, Fukaya M, Shibata T, Kurihara H, Tanaka K, Inoue Y, et al. Dynamic transformation of Bergmann glial fibers proceeds in correlation with dendritic outgrowth and synapse formation of cerebellar Purkinje cells. J Comp Neurol. 2000;418(1):106–20.

    Article  CAS  PubMed  Google Scholar 

  35. Lordkipanidze T, Dunaevsky A. Purkinje cell dendrites grow in alignment with Bergmann glia. Glia. 2005;51(3):229–34.

    Article  PubMed  Google Scholar 

  36. Dammann O, Leviton A. Role of the fetus in perinatal infection and neonatal brain damage. Curr Opin Pediatr. 2000;12(2):99–104.

    Article  CAS  PubMed  Google Scholar 

  37. Yan E, Castillo-Melendez M, Nicholls T, Hirst J, Walker D. Cerebrovascular responses in the fetal sheep brain to low-dose endotoxin. Pediatr Res. 2004;55(5):855–63.

    Article  CAS  PubMed  Google Scholar 

  38. Borges LF, Elliott PJ, Gill R, Iversen SD, Iversen LL. Selective extraction of small and large molecules from the cerebrospinal fluid by Purkinje neurons. Science. 1985;228(4697):346–8.

    Article  CAS  PubMed  Google Scholar 

  39. Fishman PS, Farrand DA, Kristt DA. Internalization of plasma proteins by cerebellar Purkinje cells. J Neurol Sci. 1990;100(1–2):43–9.

    Article  CAS  PubMed  Google Scholar 

  40. Sokrab TE, Johansson BB, Kalimo H, Olsson Y. A transient hypertensive opening of the blood–brain barrier can lead to brain damage. Extravasation of serum proteins and cellular changes in rats subjected to aortic compression. Acta Neuropathol (Berl). 1988;75(6):557–65.

    Article  CAS  Google Scholar 

  41. Brightman MW. The distribution within the brain of ferritin injected into cerebrospinal fluid compartments. I Ependymal distribution. J Cell Biol. 1965;26(1):99–123.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  42. Brightman MW. The distribution within the brain of ferritin injected into cerebrospinal fluid compartments. II. Parenchymal distribution. Am J Anat. 1965;117(2):193–219.

    Article  CAS  PubMed  Google Scholar 

  43. Mares V, Borges LF, Sidman RL. An immunocytochemical study of the binding of lectins in the developing brain in situ. Histochem J. 1984;16(4):462–4.

    Article  CAS  PubMed  Google Scholar 

  44. Tabernero A, Granda B, Medina A, Sanchez-Abarca LI, Lavado E, Medina JM. Albumin promotes neuronal survival by increasing the synthesis and release of glutamate. J Neurochem. 2002;81(4):881–91.

    Article  CAS  PubMed  Google Scholar 

  45. Dziegielewska KM, Knott GW, Saunders NR. The nature and composition of the internal environment of the developing brain. Cell Mol Neurobiol. 2000;20(1):41–56.

    Article  CAS  PubMed  Google Scholar 

  46. Heyes MP, Rubinow D, Lane C, Markey SP. Cerebrospinal fluid quinolinic acid concentrations are increased in acquired immune deficiency syndrome. Ann Neurol. 1989;26(2):275–7.

    Article  CAS  PubMed  Google Scholar 

  47. Guillemin GJ, Kerr SJ, Brew BJ. Involvement of quinolinic acid in AIDS dementia complex. Neurotox Res. 2005;7(1–2):103–23.

    Article  CAS  PubMed  Google Scholar 

  48. Guillemin GJ, Williams KR, Smith DG, Smythe GA, Croitoru-Lamoury J, Brew BJ. Quinolinic acid in the pathogenesis of Alzheimer's disease. Adv Exp Med Biol. 2003;527:167–76.

    Article  CAS  PubMed  Google Scholar 

  49. Rios C, Santamaria A. Quinolinic acid is a potent lipid peroxidant in rat brain homogenates. Neurochem Res. 1991;16(10):1139–43.

    Article  CAS  PubMed  Google Scholar 

  50. Nicholls T, Nitsos I, Walker DW. Tryptophan metabolism in pregnant sheep: increased fetal kynurenine production in response to maternal tryptophan loading. Am J Obstet Gynecol. 1999;181(6):1452–60.

    Article  CAS  PubMed  Google Scholar 

  51. Nicholls T, Lacey B, Nitsos I, Smythe G, Walker DW. Regional changes in kynurenic acid, quinolinic acid, and glial fibrillary acidic protein concentrations in the fetal sheep brain after experimentally induced placental insufficiency. Am J Obstet Gynecol. 2001;184(2):203–8.

    Article  CAS  PubMed  Google Scholar 

  52. Manuelpillai U, Ligam P, Smythe G, Wallace EM, Hirst J, Walker DW. Identification of kynurenine pathway enzyme mRNAs and metabolites in human placenta: up-regulation by inflammatory stimuli and with clinical infection. Am J Obstet Gynecol. 2005;192(1):280–8.

    Article  CAS  PubMed  Google Scholar 

  53. Yan E, Castillo-Melendez M, Smythe G, Walker D. Quinolinic acid promotes albumin deposition in Purkinje cell, astrocytic activation and lipid peroxidation in fetal brain. Neuroscience. 2005;134(3):867–75.

    Article  CAS  PubMed  Google Scholar 

  54. Goda K, Kishimoto R, Shimizu S, Hamane Y, Ueda M. Quinolinic acid and active oxygens. Possible contribution of active oxygens during cell death in the brain. Adv Exp Med Biol. 1996;398:247–54.

    Article  CAS  PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  56. Itakura A, Kurauchi O, Takashima S, Uchida K, Ito M, Mizutani S. Immunological detection of 4-hydroxynonenal protein adducts in developing pontine and Purkinje neurons and in karyorrhexis in pontosubicular neuronal necrosis. Early Hum Dev. 2002;67(1–2):19–28.

    Article  CAS  PubMed  Google Scholar 

  57. Hutton L, Castillo-Melendez M, Walker DW. Inflammatory and proliferative responses in fetal periventricular regions after utero-placental LPS administration in sheep. Los Angeles: Proc Soc Gynecol Invest Annual Meeting; 2005.

    Google Scholar 

  58. Marin-Teva JL, Dusart I, Colin C, Gervais A, van Rooijen N, Mallat M. Microglia promote the death of developing Purkinje cells. Neuron. 2004;41(4):535–47.

    Article  CAS  PubMed  Google Scholar 

  59. Phares TW, Kean RB, Mikheeva T, Hooper DC. Regional differences in blood–brain barrier permeability changes and inflammation in the apathogenic clearance of virus from the central nervous system. J Immunol. 2006;176(12):7666–75.

    Article  CAS  PubMed  Google Scholar 

  60. Zimmer C, Sampaolo S, Sharma HS, Cervos-Navarro J. Altered glial fibrillary acidic protein immunoreactivity in rat brain following chronic hypoxia. Neuroscience. 1991;40(2):353–61.

    Article  CAS  PubMed  Google Scholar 

  61. Castillo-Melendez M, Yan E, Walker DW. Expression of erythropoietin and its receptor in the brain of late-gestation fetal sheep, and responses to asphyxia caused by umbilical cord occlusion. Dev Neurosci. 2005;27(2–4):220–7.

    Article  CAS  PubMed  Google Scholar 

  62. Juul S. Erythropoietin in the central nervous system, and its use to prevent hypoxic-ischemic brain damage. Acta Paediatr Suppl. 2002;91(438):36–42.

    Article  CAS  PubMed  Google Scholar 

  63. Juul SE, Anderson DK, Li Y, Christensen RD. Erythropoietin and erythropoietin receptor in the developing human central nervous system. Pediatr Res. 1998;43(1):40–9.

    Article  CAS  PubMed  Google Scholar 

  64. Buemi M, Cavallaro E, Floccari F, Sturiale A, Aloisi C, Trimarchi M, et al. The pleiotropic effects of erythropoietin in the central nervous system. J Neuropathol Exp Neurol. 2003;62(3):228–36.

    CAS  PubMed  Google Scholar 

  65. Wen TC, Rogido M, Genetta T, Sola A. Permanent focal cerebral ischemia activates erythropoietin receptor in the neonatal rat brain. Neurosci Lett. 2004;355(3):165–8.

    Article  CAS  PubMed  Google Scholar 

  66. Nguyen PN, Yan EB, Castillo-Melendez M, Walker DW, Hirst JJ. Increased allopregnanolone levels in the fetal sheep brain following umbilical cord occlusion. J Physiol. 2004;560(Pt 2):593–602.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  67. Lauder JM. Neurotransmitters as growth regulatory signals: role of receptors and second messengers. Trends Neurosci. 1993;16(6):233–40.

    Article  CAS  PubMed  Google Scholar 

  68. Fiszman ML, Behar T, Lange GD, Smith SV, Novotny EA, Barker JL. GABAergic cells and signals appear together in the early post-mitotic period of telencephalic and striatal development. Brain Res Dev Brain Res. 1993;73(2):243–51.

    Article  CAS  PubMed  Google Scholar 

  69. Mandler RN, Schaffner AE, Novotny EA, Lange GD, Smith SV, Barker JL. Electrical and chemical excitability appear one week before birth in the embryonic rat spinal cord. Brain Res. 1990;522(1):46–54.

    Article  CAS  PubMed  Google Scholar 

  70. Schaffner AE, Behar T, Nadi S, Smallwood V, Barker JL. Quantitative analysis of transient GABA expression in embryonic and early postnatal rat spinal cord neurons. Brain Res Dev Brain Res. 1993;72(2):265–76.

    Article  CAS  PubMed  Google Scholar 

  71. Bailey CD, Brien JF, Reynolds JN. Neurosteroid modulation of the GABAA receptor in the developing guinea pig cerebral cortex. Brain Res Dev Brain Res. 1999;113(1–2):21–8.

    Article  CAS  PubMed  Google Scholar 

  72. Shen H, Gong QH, Yuan M, Smith SS. Short-term steroid treatment increases delta GABAA receptor subunit expression in rat CA1 hippocampus: pharmacological and behavioral effects. Neuropharmacology. 2005;49(5):573–86.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  73. Compagnone NA, Mellon SH. Neurosteroids: biosynthesis and function of these novel neuromodulators. Front Neuroendocrinol. 2000;21(1):1–56.

    Article  CAS  PubMed  Google Scholar 

  74. Paul SM, Purdy RH. Neuroactive steroids. Faseb J. 1992;6(6):2311–22.

    CAS  PubMed  Google Scholar 

  75. Lambert JJ, Belelli D, Hill-Venning C, Peters JA. Neurosteroids and GABAA receptor function. Trends Pharmacol Sci. 1995;16(9):295–303.

    Article  CAS  PubMed  Google Scholar 

  76. Petratos S, Hirst JJ, Mendis S, Anikijenko P, Walker DW. Localization of p450scc and 5alpha-reductase type-2 in the cerebellum of fetal and newborn sheep. Brain Res Dev Brain Res. 2000;123(1):81–6.

    Article  CAS  PubMed  Google Scholar 

  77. Nguyen PN, Billiards SS, Walker DW, Hirst JJ. Changes in 5alpha-pregnane steroids and neurosteroidogenic enzyme expression in fetal sheep with umbilicoplacental embolization. Pediatr Res. 2003;54(6):840–7.

    Article  CAS  PubMed  Google Scholar 

  78. Nguyen PN, Billiards SS, Walker DW, Hirst JJ. Changes in 5alpha-pregnane steroids and neurosteroidogenic enzyme expression in the perinatal sheep. Pediatr Res. 2003;53(6):956–64.

    Article  CAS  PubMed  Google Scholar 

  79. Fritschy JM, Mohler H. GABAA-receptor heterogeneity in the adult rat brain: differential regional and cellular distribution of seven major subunits. J Comp Neurol. 1995;359(1):154–94.

    Article  CAS  PubMed  Google Scholar 

  80. Laurie DJ, Wisden W, Seeburg PH. The distribution of thirteen GABAA receptor subunit mRNAs in the rat brain. III. Embryonic and postnatal development. J Neurosci. 1992;12(11):4151–72.

    CAS  PubMed  Google Scholar 

  81. Yawno, T, Walker, DW and Hirst, JJ, Inhibition of neurosteroid synthesis increases asphyxia-induced brain injury in late gestation fetal sheep. Proc. Soc. Gynecol. Invest. Annual Meeting, 2006.

Download references

Author information

Authors and Affiliations

  1. Monash Biomedical Imaging, Monash University, Clayton, Victoria, 3800, Australia

    Lisa C. Hutton

  2. Department of Physiology, Monash University, Clayton, Victoria, 3800, Australia

    Edwin Yan

  3. The Ritchie Centre, MIMR-PHI Institute of Medical Research, Clayton, Victoria, 3168, Australia

    Tamara Yawno, Margie Castillo-Melendez & David W. Walker

  4. School of Biomedical Sciences, University of Newcastle, Callaghan, New South Wales, 2308, Australia

    Jon J. Hirst

  5. Department of Obstetrics & Gynaecology, Monash University, Monash Medical Centre, Clayton, Victoria, 3168, Australia

    David W. Walker

Authors
  1. Lisa C. Hutton
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Edwin Yan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tamara Yawno
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Margie Castillo-Melendez
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jon J. Hirst
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. David W. Walker
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to David W. Walker.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hutton, L.C., Yan, E., Yawno, T. et al. Injury of the Developing Cerebellum: A Brief Review of the Effects of Endotoxin and Asphyxial Challenges in the Late Gestation Sheep Fetus. Cerebellum 13, 777–786 (2014). https://doi.org/10.1007/s12311-014-0602-3

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12311-014-0602-3

Keywords

Search

Navigation