Skip to main content
NCBI home page
Neuroscience Bulletin logoLink to Neuroscience Bulletin
. 2013 Feb 28;29(2):229–238. doi: 10.1007/s12264-013-1311-5

Vulnerability of premyelinating oligodendrocytes to white-matter damage in neonatal brain injury

Xiao-Bo Liu 1, Yan Shen 1, Jennifer M Plane 1, Wenbin Deng 1,✉
PMCID: PMC5561874  PMID: 23456565

Abstract

Premature birth is a significant economic and public health burden, and its incidence is rising. Periventricular leukomalacia (PVL) is the predominant form of brain injury in premature infants and the leading cause of cerebral palsy. PVL is characterized by selective white-matter damage with prominent oligodendroglial injury. The maturation-dependent vulnerability of developing and premyelinating oligodendrocytes to excitotoxic, oxidative, and inflammatory forms of injury is a major factor in the pathogenesis of PVL. Recent studies using mouse models of PVL reveal that synapses between axons and developing oligodendrocytes are quickly and profoundly damaged in immature white matter. Axon-glia synapses are highly vulnerable to white-matter injury in the developing brain, and the loss of synapses between axons and premyelinating oligodendrocytes occurs before any cellular loss in the immature white matter. Microglial activation and astrogliosis play important roles in triggering white-matter injury. Impairment of white-matter development and function in the neonatal period contributes critically to functional and behavioral deficits. Preservation of the integrity of the white matter is likely key in the treatment of PVL and subsequent neurological consequences and disabilities.

Keywords: prematurity, neonatal brain injury, white matter, oligodendrocyte, myelin, periventricular leukomalacia

References

  • [1].Hack M, Wilson-Costello D, Friedman H, Taylor GH, Schluchter M, Fanaroff AA. Neurodevelopment and predictors of outcomes of children with birth weights of less than 1000 g: 1992–1995. Arch Pediatr Adolesc Med. 2000;154:725–731. doi: 10.1001/archpedi.154.7.725. [DOI] [PubMed] [Google Scholar]
  • [2].Silbereis JC, Huang EJ, Back SA, Rowitch DH. Towards improved animal models of neonatal white matter injury associated with cerebral palsy. Dis Model Mech. 2010;3:678–688. doi: 10.1242/dmm.002915. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [3].Titomanlio L, Kavelaars A, Dalous J, Mani S, El Ghouzzi V, Heijnen C, et al. Stem cell therapy for neonatal brain injury: perspectives and challenges. Ann Neurol. 2011;70:698–712. doi: 10.1002/ana.22518. [DOI] [PubMed] [Google Scholar]
  • [4].Volpe JJ. Neurology of the Newborn. 4th ed. Philadelphia: WB Saunders; 2001. pp. 217–276. [Google Scholar]
  • [5].Volpe JJ. Brain injury in premature infants: a complex amalgam of destructive and developmental disturbances. Lancet Neurol. 2009;8:110–124. doi: 10.1016/S1474-4422(08)70294-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [6].Banker BQ, Larroche JC. Periventricular leukomalacia of infancy. A form of neonatal anoxic encephalopathy. Arch Neurol. 1962;7:386–410. doi: 10.1001/archneur.1962.04210050022004. [DOI] [PubMed] [Google Scholar]
  • [7].Leviton A, Gilles FH. Acquired perinatal leukoencephalopathy. Ann Neurol. 1984;16:1–8. doi: 10.1002/ana.410160102. [DOI] [PubMed] [Google Scholar]
  • [8].Gilles FH, Averill DR, Jr, Kerr CS. Neonatal endotoxin encephalopathy. Ann Neurol. 1977;2:49–56. doi: 10.1002/ana.410020108. [DOI] [PubMed] [Google Scholar]
  • [9].Deng W, Pleasure J, Pleasure D. Progress in periventricular leukomalacia. Arch Neurol. 2008;65:1291–1295. doi: 10.1001/archneur.65.10.1291. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [10].Pleasure D, Soulika A, Singh SK, Gallo V, Bannerman P. Inflammation in white matter: clinical and pathophysiological aspects. Ment Retard Dev Disabil Res Rev. 2006;12:141–146. doi: 10.1002/mrdd.20100. [DOI] [PubMed] [Google Scholar]
  • [11].Deng W. Neurobiology of injury to the developing brain. Nat Rev Neurol. 2010;6:328–336. doi: 10.1038/nrneurol.2010.53. [DOI] [PubMed] [Google Scholar]
  • [12].Back SA, Luo NL, Borenstein NS, Levine JM, Volpe JJ, Kinney HC. Late oligodendrocyte progenitors coincide with the developmental window of vulnerability for human perinatal white matter injury. J Neurosci. 2001;21:1302–1312. doi: 10.1523/JNEUROSCI.21-04-01302.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [13].Kinney HC, Back SA. Human oligodendroglial development: relationship to periventricular leukomalacia. Semin Pediatr Neurol. 1998;5:180–189. doi: 10.1016/S1071-9091(98)80033-8. [DOI] [PubMed] [Google Scholar]
  • [14].Levine JM, Reynolds R, Fawcett JW. The oligodendrocyte precursor cell in health and disease. Trends Neurosci. 2001;24:39–47. doi: 10.1016/S0166-2236(00)01691-X. [DOI] [PubMed] [Google Scholar]
  • [15].Pfeiffer SE, Warrington AE, Bansal R. The oligodendrocyte and its many cellular processes. Trends Cell Biol. 1993;3:191–197. doi: 10.1016/0962-8924(93)90213-K. [DOI] [PubMed] [Google Scholar]
  • [16].Raff MC, Miller RH, Noble M. A glial progenitor cell that develops in vitro into an astrocyte or an oligodendrocyte depending on culture medium. Nature. 1983;303:390–396. doi: 10.1038/303390a0. [DOI] [PubMed] [Google Scholar]
  • [17].Deng W, Poretz RD. Oligodendroglia in developmental neurotoxicity. Neurotoxicology. 2003;24:161–178. doi: 10.1016/S0161-813X(02)00196-1. [DOI] [PubMed] [Google Scholar]
  • [18].Oka A, Belliveau MJ, Rosenberg PA, Volpe JJ. Vulnerability of oligodendroglia to glutamate: pharmacology, mechanisms, and prevention. J Neurosci. 1993;13:1441–1453. doi: 10.1523/JNEUROSCI.13-04-01441.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [19].DeSilva TM, Kabakov AY, Goldhoff PE, Volpe JJ, Rosenberg PA. Regulation of glutamate transport in developing rat oligodendrocytes. J Neurosci. 2009;29:7898–7908. doi: 10.1523/JNEUROSCI.6129-08.2009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [20].Back SA, Craig A, Kayton RJ, Luo NL, Meshul CK, Allcock N, et al. Hypoxia-ischemia preferentially triggers glutamate depletion from oligodendroglia and axons in perinatal cerebral white matter. J Cereb Blood Flow Metab. 2007;27:334–347. doi: 10.1038/sj.jcbfm.9600344. [DOI] [PubMed] [Google Scholar]
  • [21].Desilva TM, Kinney HC, Borenstein NS, Trachtenberg FL, Irwin N, Volpe JJ, et al. The glutamate transporter EAAT2 is transiently expressed in developing human cerebral white matter. J Comp Neurol. 2007;501:879–890. doi: 10.1002/cne.21289. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [22].Shen Y, Liu XB, Pleasure DE, Deng W. Axon-glia synapses are highly vulnerable to white matter injury in the developing brain. J Neurosci Res. 2012;90:105–121. doi: 10.1002/jnr.22722. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [23].Shen Y, Plane JM, Deng W. J Vis Exp. 2010. Mouse models of periventricular leukomalacia. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [24].Lehnardt S, Henneke P, Lien E, Kasper DL, Volpe JJ, Bechmann I, et al. A mechanism for neurodegeneration induced by group B streptococci through activation of the TLR2/MyD88 pathway in microglia. J Immunol. 2006;177:583–592. doi: 10.4049/jimmunol.177.1.583. [DOI] [PubMed] [Google Scholar]
  • [25].Lehnardt S, Lachance C, Patrizi S, Lefebvre S, Follett PL, Jensen FE, et al. The toll-like receptor TLR4 is necessary for lipopolysaccharide-induced oligodendrocyte injury in the CNS. J Neurosci. 2002;22:2478–2486. doi: 10.1523/JNEUROSCI.22-07-02478.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [26].Billiards SS, Haynes RL, Folkerth RD, Trachtenberg FL, Liu LG, Volpe JJ, et al. Development of microglia in the cerebral white matter of the human fetus and infant. J Comp Neurol. 2006;497:199–208. doi: 10.1002/cne.20991. [DOI] [PubMed] [Google Scholar]
  • [27].Pitt D, Nagelmeier IE, Wilson HC, Raine CS. Glutamate uptake by oligodendrocytes: Implications for excitotoxicity in multiple sclerosis. Neurology. 2003;61:1113–1120. doi: 10.1212/01.WNL.0000090564.88719.37. [DOI] [PubMed] [Google Scholar]
  • [28].Wender R, Brown AM, Fern R, Swanson RA, Farrell K, Ransom BR. Astrocytic glycogen influences axon function and survival during glucose deprivation in central white matter. J Neurosci. 2000;20:6804–6810. doi: 10.1523/JNEUROSCI.20-18-06804.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [29].Dingledine R, Borges K, Bowie D, Traynelis SF. The glutamate receptor ion channels. Pharmacol Rev. 1999;51:7–61. [PubMed] [Google Scholar]
  • [30].Lipton SA, Rosenberg PA. Excitatory amino acids as a final common pathway for neurologic disorders. N Engl J Med. 1994;330:613–622. doi: 10.1056/NEJM199403033300907. [DOI] [PubMed] [Google Scholar]
  • [31].Itoh T, Beesley J, Itoh A, Cohen AS, Kavanaugh B, Coulter DA, et al. AMPA glutamate receptor-mediated calcium signaling is transiently enhanced during development of oligodendrocytes. J Neurochem. 2002;81:390–402. doi: 10.1046/j.1471-4159.2002.00866.x. [DOI] [PubMed] [Google Scholar]
  • [32].Matute C, Sanchez-Gomez MV, Martinez-Millan L, Miledi R. Glutamate receptor-mediated toxicity in optic nerve oligodendrocytes. Proc Natl Acad Sci U S A. 1997;94:8830–8835. doi: 10.1073/pnas.94.16.8830. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [33].McDonald JW, Althomsons SP, Hyrc KL, Choi DW, Goldberg MP. Oligodendrocytes from forebrain are highly vulnerable to AMPA/kainate receptor-mediated excitotoxicity. Nat Med. 1998;4:291–297. doi: 10.1038/nm0398-291. [DOI] [PubMed] [Google Scholar]
  • [34].Yoshioka A, Bacskai B, Pleasure D. Pathophysiology of oligodendroglial excitotoxicity. J Neurosci Res. 1996;46:427–437. doi: 10.1002/(SICI)1097-4547(19961115)46:4<427::AID-JNR4>3.0.CO;2-I. [DOI] [PubMed] [Google Scholar]
  • [35].Fern R, Moller T. Rapid ischemic cell death in immature oligodendrocytes: a fatal glutamate release feedback loop. J Neurosci. 2000;20:34–42. doi: 10.1523/JNEUROSCI.20-01-00034.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [36].Follett PL, Deng W, Dai W, Talos DM, Massillon LJ, Rosenberg PA, et al. Glutamate receptor-mediated oligodendrocyte toxicity in periventricular leukomalacia: a protective role for topiramate. J Neurosci. 2004;24:4412–4420. doi: 10.1523/JNEUROSCI.0477-04.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [37].Follett PL, Rosenberg PA, Volpe JJ, Jensen FE. NBQX attenuates excitotoxic injury in developing white matter. J Neurosci. 2000;20:9235–9241. doi: 10.1523/JNEUROSCI.20-24-09235.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [38].Deng W, Neve RL, Rosenberg PA, Volpe JJ, Jensen FE. Alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor subunit composition and cAMP-response elementbinding protein regulate oligodendrocyte excitotoxicity. J Biol Chem. 2006;281:36004–36011. doi: 10.1074/jbc.M606459200. [DOI] [PubMed] [Google Scholar]
  • [39].Deng W, Rosenberg PA, Volpe JJ, Jensen FE. Calcium-permeable AMPA/kainate receptors mediate toxicity and preconditioning by oxygen-glucose deprivation in oligodendrocyte precursors. Proc Natl Acad Sci U S A. 2003;100:6801–6806. doi: 10.1073/pnas.1136624100. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [40].Deng W, Wang H, Rosenberg PA, Volpe JJ, Jensen FE. Role of metabotropic glutamate receptors in oligodendrocyte excitotoxicity and oxidative stress. Proc Natl Acad Sci U S A. 2004;101:7751–7756. doi: 10.1073/pnas.0307850101. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [41].Karadottir R, Cavelier P, Bergersen LH, Attwell D. NMDA receptors are expressed in oligodendrocytes and activated in ischaemia. Nature. 2005;438:1162–1166. doi: 10.1038/nature04302. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [42].Micu I, Jiang Q, Coderre E, Ridsdale A, Zhang L, Woulfe J, et al. NMDA receptors mediate calcium accumulation in myelin during chemical ischaemia. Nature. 2006;439:988–992. doi: 10.1038/nature04474. [DOI] [PubMed] [Google Scholar]
  • [43].Salter MG, Fern R. NMDA receptors are expressed in developing oligodendrocyte processes and mediate injury. Nature. 2005;438:1167–1171. doi: 10.1038/nature04301. [DOI] [PubMed] [Google Scholar]
  • [44].Haynes RL, Baud O, Li J, Kinney HC, Volpe JJ, Folkerth DR. Oxidative and nitrative injury in periventricular leukomalacia: a review. Brain Pathol. 2005;15:225–233. doi: 10.1111/j.1750-3639.2005.tb00525.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [45].Haynes RL, Folkerth RD, Keefe RJ, Sung I, Swzeda LI, Rosenberg PA, et al. Nitrosative and oxidative injury to premyelinating oligodendrocytes in periventricular leukomalacia. J Neuropathol Exp Neurol. 2003;62:441–450. doi: 10.1093/jnen/62.5.441. [DOI] [PubMed] [Google Scholar]
  • [46].Griffiths M, Neal JW, Gasque P. Innate immunity and protective neuroinflammation: new emphasis on the role of neuroimmune regulatory proteins. Int Rev Neurobiol. 2007;82:29–55. doi: 10.1016/S0074-7742(07)82002-2. [DOI] [PubMed] [Google Scholar]
  • [47].Glezer I, Zekki H, Scavone C, Rivest S. Modulation of the innate immune response by NMDA receptors has neuropathological consequences. J Neurosci. 2003;23:11094–11103. doi: 10.1523/JNEUROSCI.23-35-11094.2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [48].Lechpammer M, Manning SM, Samonte F, Nelligan J, Sabo E, Talos DM, et al. Minocycline treatment following hypoxic/ischaemic injury attenuates white matter injury in a rodent model of periventricular leucomalacia. Neuropathol Appl Neurobiol. 2008;34:379–393. doi: 10.1111/j.1365-2990.2007.00925.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [49].Liu W, Shen Y, Plane JM, Pleasure DE, Deng W. Neuroprotective potential of erythropoietin and its derivative carbamylated erythropoietin in periventricular leukomalacia. Exp Neurol. 2011;230:227–239. doi: 10.1016/j.expneurol.2011.04.021. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [50].Fields RD. Myelination: an overlooked mechanism of synaptic plasticity? Neuroscientist. 2005;11:528–531. doi: 10.1177/1073858405282304. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [51].Anjari M, Srinivasan L, Allsop JM, Hajnal JV, Rutherford MA, Edwards AD, et al. Diffusion tensor imaging with tract-based spatial statistics reveals local white matter abnormalities in preterm infants. Neuroimage. 2007;35:1021–1027. doi: 10.1016/j.neuroimage.2007.01.035. [DOI] [PubMed] [Google Scholar]
  • [52].Arzoumanian Y, Mirmiran M, Barnes PD, Woolley K, Ariagno RL, Moseley ME, et al. Diffusion tensor brain imaging findings at term-equivalent age may predict neurologic abnormalities in low birth weight preterm infants. AJNR Am J Neuroradiol. 2003;24:1646–1653. [PMC free article] [PubMed] [Google Scholar]
  • [53].Inder TE, Huppi PS, Warfield S, Kikinis R, Zientara GP, Barnes PD, et al. Periventricular white matter injury in the premature infant is followed by reduced cerebral cortical gray matter volume at term. Ann Neurol. 1999;46:755–760. doi: 10.1002/1531-8249(199911)46:5<755::AID-ANA11>3.0.CO;2-0. [DOI] [PubMed] [Google Scholar]
  • [54].Inder TE, Wells SJ, Mogridge NB, Spencer C, Volpe JJ. Defining the nature of the cerebral abnormalities in the premature infant: a qualitative magnetic resonance imaging study. J Pediatr. 2003;143:171–179. doi: 10.1067/S0022-3476(03)00357-3. [DOI] [PubMed] [Google Scholar]
  • [55].Peterson BS, Vohr B, Staib LH, Cannistraci CJ, Dolberg A, Schneider KC, et al. Regional brain volume abnormalities and long-term cognitive outcome in preterm infants. JAMA. 2000;284:1939–1947. doi: 10.1001/jama.284.15.1939. [DOI] [PubMed] [Google Scholar]

Articles from Neuroscience Bulletin are provided here courtesy of Springer

RESOURCES