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. 2006 Apr 5;11(1):56–71. doi: 10.1111/j.1750-3639.2001.tb00381.x

Central Role of Microglia in Neonatal Excitotoxic Lesions of the Murine Periventricular White Matter

SL Tahraoui 1, S Marret 2, C Bodénant 3, P Leroux 2, MA Dommergues 1, P Evrard 1, P Gressens 1,✉
PMCID: PMC8098534  PMID: 11145204

Abstract

Periventricular leukomalacia (PVL) is the main cause of neurologic handicap in pre‐term infants. The understanding of cellular and molecular mechanisms leading to white matter damage is critical for development of innovative therapeutic strategies for PVL. The pathogenesis of PVL remains unclear but possibly involves glutamate excitotoxicity as an important molecular pathway. We previously described a neonatal mouse model of excitotoxic white matter lesion mimicking human PVL. In the present study, we used this experimental tool to investigate the cellular populations and the glutamate receptor subtypes involved in excitotoxic white matter lesions. Combined immunohistochemical, electron microscopic, and cell death detection data revealed that microglial activation and astrocytic death were the primary responses of white matter to excitotoxic insult. In vitro experiments suggested that microglia activated by ibotenate released soluble factors that kill astrocytes. The use of selective agonists and antagonists of glutamate receptors revealed that N‐methyl‐D‐aspartate (NMDA) receptor activation was essential and sufficient to produce cystic white matter lesions. NMDA receptor immunohistochemistry labeled microglial cells in the neonatal periventricular white matter. The developing white matter displayed a window of sensitivity to excitotoxic damage that was paralleled by the transient presence of NMDA receptor‐expressing white matter cells. Assuming that similar pathophysiologic mechanisms are present in human pre‐ term infants, microglia and NMDA receptors could represent key targets for treatment of PVL.

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References

  • 1. Bac P, Maurois P, Dupont C, Pages N, Stables JP, Gressens P, Evrard P, Vamecq J (1998) Magnesium‐deficiency‐dependent audiogenic seizures (MDDASs) in adult mice: A nutritional model for discriminatory screening of anticonvulsant drugs and original assessment of neuroprotection properties. J Neurosci 18: 4363–4373. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2. Back SA, Gan X, Li Y, Rosenbaum PA, Volpe JJ (1998) Maturation‐dependent vulnerability of oligodendrocytes to oxidative stress‐induced death caused by glutathione depletion. J Neurosci 18: 6241–6253. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3. Barron KD (1995) The microglial cell. A historical review. J Neurol Sci 134 (Suppl): 57–68. [DOI] [PubMed] [Google Scholar]
  • 4. Benveniste EN (1997) Role of macrophages/microglia in multiple sclerosis and experimental allergic encephalomyelitis. J Mol Med 75: 165–173. [DOI] [PubMed] [Google Scholar]
  • 5. Brenneman D, Nicol T, Warren D, Bowers L (1990) Vasoactive intestinal peptide: A neurotrophic releasing agent and an astroglial mitogen. J Neurosci Res 25: 386–394. [DOI] [PubMed] [Google Scholar]
  • 6. Brückner G, Biesold D (1981) Histochemistry of glycogen deposition in perinatal rat brain: importance of radial glial cells. J Neurocytol 10: 749–757. [DOI] [PubMed] [Google Scholar]
  • 7. Coffey PJ, Perry VH, Rawlins JNP (1990) An investigation into the early stages of the inflammatory response following ibotenic acidinduced neuronal degeneration. Neurosci 35: 121–132. [DOI] [PubMed] [Google Scholar]
  • 8. Cole R, De Vellis J (1989) Preparation of astrocyte and oligodendrocyte cultures from primary rat glial cultures In: A dissection and tissue culture manual of the nervous system, Shabar A, De Vellis J, Vernadakis A, Haber B (eds), PP. 121–133, Liss: New York . [Google Scholar]
  • 9. Debillon T, Gras‐Leguen C, Vérielle V, Winer N, Caillon J, Roze JC, Gressens P (1999) Intrauterine infection induces periventricular cell death in rabbits. Pediatr Res, In Press. [DOI] [PubMed] [Google Scholar]
  • 10. Deguchi K, Mizuguchi M, Takashima S (1996) Immunohistochemical expression of tumor necrosis factor alpha in neonatal leukomalacia. Pediatr Neurol 14: 13–16. [DOI] [PubMed] [Google Scholar]
  • 11. Dommergues MA, Gallego J, Evrard P, Gressens P (1998) Iron supplementation aggravates periventricular cystic white matter lesion in newborn mice. Eur J Paediatr Neurol 2: 313–318. [DOI] [PubMed] [Google Scholar]
  • 12. Dommergues MA, Patkai J, Renauld JC, Evrard P, Gressens P (2000) Pro‐inflammatory cytokines and IL‐9 exacerbate excitotoxic lesions of the newborn murine neopallium. Ann Neurol 47: 54–63. [PubMed] [Google Scholar]
  • 13. Earle KL, Mitrofanis J (1997) Identification of transient microglial cell colonies in the forebrain white matter of developing rats. J Comp Neurol 387:371–384. [DOI] [PubMed] [Google Scholar]
  • 14. Evrard P, Marret S, Gressens P (1997) Environmental and genetic determinants of neural migration and postmigratory survival. Acta Paediatr Scandinav Suppl 5: 20–26. [DOI] [PubMed] [Google Scholar]
  • 15. Gadisseux JF, Evrard P (1985) Glial‐neuronal relationship in the developing nervous system. Dev Neurosci 7: 12–32. [DOI] [PubMed] [Google Scholar]
  • 16. Gilles FH, Averill D, Kerre CS (1977) Neonatal endotoxin encephalopathy. Ann Neurol 2: 49–56. [DOI] [PubMed] [Google Scholar]
  • 17. Gilmore EC, Nowakowski RS, Caviness VS, Herrup K (2000) Cell birth, cell death, cell diversity and DNA breaks: how do they fit all together Trends Neurol Sci 23:100–105. [DOI] [PubMed] [Google Scholar]
  • 18. Gressens P, Marret S, Hill JM, Brenneman DE, Gozes I, Fridkin M (1997) Vasoactive intestinal peptide prevents excitotoxic cell death in the murine developing brain. J Clin Invest 100: 390–397. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19. Gressens P, Marret S, Martin JL, Laquerrière A, Lombet A, Evrard P (1998) Regulation of neuroprotective action of vasoactive intestinal peptide in the murine developing brain by protein kinase C and mitogen‐activated protein kinase cascades: In vivo and in vitro studies. J Neurochem 70: 2574–2584. [DOI] [PubMed] [Google Scholar]
  • 20. Gressens P, Martin JR (1994) In situ polymerase chain reaction to localize infectious and latent herpes simplex DNA in murine central nervous system. J Virol Meth 46: 61–83. [DOI] [PubMed] [Google Scholar]
  • 21. Gressens P, Martin JR. (1994) HSV‐2 persistence in CNS non‐neuronal cells of the trigeminal root entry zone: Double labeling by immunohistochemistry and in situ polymerase chain reaction. J Neuropathol Exp Neurol 53:127–135. [DOI] [PubMed] [Google Scholar]
  • 22. Gressens P, Richelme Ch, Kadhim HJ, Gadisseux JF, Evrard P (1992) The germinative zone produces most cortical astrocytes after neuronal migration in developing mammalian brain. Biol Neonate 61: 4–24. [DOI] [PubMed] [Google Scholar]
  • 23. Hagberg B, Hagberg G, Olow I, Wendt L (1996) The changing panorama of cerebral palsy in Sweden. VII. Prevalence and origin in the birth year period 1987–90. Acta Paediatr 85: 954–960. [DOI] [PubMed] [Google Scholar]
  • 24. Lasorella A, Ivavarone A, Israel MA (1995) Differentiation of neuroblastoma enhances Bcl‐2 expression and induces alterations of apoptosis and drug resistance. Cancer Res 55: 4711–4716. [PubMed] [Google Scholar]
  • 25. Lipton SA, Rosenberg PA (1994) Excitatory amino acids as a final common pathway for neurologic disorders. N Engl J Med 330: 613–622. [DOI] [PubMed] [Google Scholar]
  • 26. Marret S, Bonnier C, Raymaekers JM, Delpech A, Evrard P, Gressens P (1999) Systemic administration of antiNOS and anti‐glycine protects against excitotoxic lesions in the developing mouse brain. Pediatr Res 45: 337–342. [DOI] [PubMed] [Google Scholar]
  • 27. Marret S, Gadisseux JF, Gressens P, Evrard P (1995) Prevention by magnesium of excitotoxic neuronal death in developing brain. An animal model for the clinical intervention studies. Dev Med Child Neurol 37: 473–484. [DOI] [PubMed] [Google Scholar]
  • 28. Marret S, Gressens P, Evrard P (1996) Arrest of neuronal migration by excitatory amino acids in hamster developing brain. Proc Natl Acad Sci USA 93: 15463–15468. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29. Marret S, Mukendi R, Gadisseux JF, Gressens P, Evrard P (1995) Effect of ibotenate on brain development: An excitotoxic mouse model of microgyria and posthypoxiclike lesions. J Neuropathol Exp Neurol 54: 358–370. [DOI] [PubMed] [Google Scholar]
  • 30. Marty S, Dussart I, Peschanski M (1991) Glial changes following an excitotoxic lesion in the CNS ‐ I. Microglia/macrophages. Neurosci 45: 529–539. [DOI] [PubMed] [Google Scholar]
  • 31. Matute C, Sanchez‐Gomez MV, Martinez‐Milan L, Miledi R (1997) Glutamate receptor‐mediated toxicity in optic nerve oligodendrocytes. Proc Natl Acad Sci USA 94: 8830–8835. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32. Maxwell M (1978) An on‐grid method for the specific demonstration of glycogen in electron microscopy. Med Lab Sci 35: 201–202. [PubMed] [Google Scholar]
  • 33. McDonald JW, Althomsons SP, Hyrc KL, Choi DW, Goldberg MP (1998) Oligodendrocytes are highly vulnerable to AMPA/kainate receptor‐mediated excitotoxicity. Nature Med 4: 291–297. [DOI] [PubMed] [Google Scholar]
  • 34. McDonald JW, Johnston MV (1990) Physiological and pathophysiological roles of excitatory amino acids during central nervous system development. Brain Res Rev 15:41–70. [DOI] [PubMed] [Google Scholar]
  • 35. McMorris FA, Smith TM, DeSalvo S, Furlanetto RW (1986) Insulin‐like growth factor I/somatomedin C: A potent inducer of oligodendrocyte development. Proc Nat Acad Sci USA 83: 822–826. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36. McRae A, Gilland E, Bona E, Hagberg H (1995) Microglia activation after neonatal hypoxic‐ischemia. Dev Brain Res 84: 245–252. [DOI] [PubMed] [Google Scholar]
  • 37. Minghetti L, Levi G (1998) Microglia as effector cells in brain damage and repair: Focus on prostanoids and nitric oxide. Prog Neurobiol 54: 99–125. [DOI] [PubMed] [Google Scholar]
  • 38. Murphy DJ, Sellers S, MacKenzie IZ, Yudkin PL, Johnson AM (1995) Case‐control study of antenatal and intrapartum risk factors for cerebral palsy in very preterm singleton babies. Lancet 346:1449–1454. [DOI] [PubMed] [Google Scholar]
  • 39. Nelson KB, Ellenberg JH (1986) Antecedents of cerebral palsy. Multivariate analysis of risk. N Engl J Med 315: 81–86. [DOI] [PubMed] [Google Scholar]
  • 40. Oka A, Beliveau MJ, Rosenberg PA, Volpe JJ (1993) Vulnerability of oligodendroglia to glutamate: Pharmacology, mechanisms, and prevention. J Neurosci 13: 1441–1453. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41. Redecker C, Hagemann G, Marret S, Evrard P, Witte OW, Gressens P (1998) Long‐term evolution of excitotoxic cortical dysgenesis induced in the developing rat brain. Dev Brain Res 109: 109–113. [DOI] [PubMed] [Google Scholar]
  • 42. Redecker C, Lutzenburg M, Gressens P, Evrard P, Witte OW, Hagemann G (1998) Patterns of excitability changes and glucose metabolism in experimentally induced cortical dysplasias. Cereb Cortex 8: 623–634. [DOI] [PubMed] [Google Scholar]
  • 43. Rorke LB (1992) Perinatal brain damage In: Greenfield's neuropathology, 5th Edition, Adams JH, Duchen LW (eds), pp 639–709, Edward Arnold: London . [Google Scholar]
  • 44. Silver J, Lorenz SE, Whalsten D, Coughlin J (1982) Axonal guidance during development of the great cerebral commissures: Descriptive and experimental studies, in vivo, on the role of preformed glial pathways. J Comp Neurol 210: 10–29. [DOI] [PubMed] [Google Scholar]
  • 45. Sotelo C, Palay SL (1968) The fine structure of the lateral vestibular nucleus in the rat. I. Neurons and neuroglial cells. J Cell Biol 36: 151–179. [PubMed] [Google Scholar]
  • 46. Spassky N, Goujet‐Zalc C, Parmantier E, Olivier C, Martinez S, Ivanova A, Ikenaka K, Macklin W, Cerruti I, Zalc B, Thomas JL (1998) Multiple restricted origin of oligodendrocytes. J Neurosci 15:8331–8343. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47. Szaflarski J, Ivacko J, Liu XH, Warren JS, Silverstein FS (1998) Excitotoxic injury induces monocyte chemoattractant protein‐1 expression in neonatal rat brain. Mol Brain Res 55:306–314. [DOI] [PubMed] [Google Scholar]
  • 48. Tammamaki N, Fujimori KE, Takauji R (1997). Origin and route of tangentially migrating neurons in the developing neocortical intermediate zone. J Neurosci 17: 8313–23. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 49. Tanaka H, Obata K (1982) Survival and neurite outgrowth of chick embryo spinal cord cells in serum‐free culture. Dev Brain Res 4: 313–321. [DOI] [PubMed] [Google Scholar]
  • 50. Volpe JJ (1995) Neurology of the newborn, WB Saunders Company: Philadelphia . [Google Scholar]
  • 51. Volpe J J (1997) Brain injury in the premature infant ‐ from pathogenesis to prevention. Brain Dev 19:519–534. [DOI] [PubMed] [Google Scholar]
  • 52. Wang C, Pralong WF, Schulz MF, Rougon G, Aubry JM, Pagliusi S, Robert A, Kiss JZ (1996) Functional N‐methylD‐aspartate receptors in O‐2A glial precursor cells: A critical role in regulating polysialic acid‐neural cell adhesion molecule expression and cell migration. J Cell Biol 135: 1565–1581. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 53. Wood P, Bunge RP (1984) The biology of the oligodendrocyte In: Oligodendroglia, Advances in Neurochemistry., Vol. 5, Norton WT (Ed), pp. 1–46, Plenum: New York . [Google Scholar]
  • 54. Yonezawa M, Back SA, Gan X, Rosenberg PA, Volpe J (1996) Cystine deprivation induces oligodendroglial death: Rescue by free radical scavengers and by a diffusible glial factor. J Neurochem 67: 566–573. [DOI] [PubMed] [Google Scholar]
  • 55. Yoon BH, Kim CJ, Romero R, Jun JK, Park KH, Choi ST, Chi JG (1997) Experimentally induced intrauterine infection causes fetal brain white matter lesions in rabbits. Am J Obstet Gynecol 177: 797–802. [DOI] [PubMed] [Google Scholar]
  • 56. Yoon BH, Romero R, Kim CJ, Koo JN, Choe G, Syn HC, Chi JG (1997) High expression of tumor necrosis factor‐alpha and interleukin‐6 in periventricular leukomalacia. Am J Obstet Gynecol 177: 406–411. [DOI] [PubMed] [Google Scholar]
  • 57. Yoon BH, Romero R, Yang SH, Jun JK, Kim IO, Choi JH, Syn HC (1996) Interleukin‐6 concentrations in umbilical cord plasma are elevated in neonates with white matter lesions associated with periventricular leukomalacia. Am J Obstet Gynecol 174: 1433–1440. [DOI] [PubMed] [Google Scholar]
  • 58. Yoshioka H, Goma H, Nioka S, Ochi M, Miyake M, Zaman A (1994) Bilateral carotid occlusion causes periventricular leukomalacia in neonatal dogs. Dev Brain Res 78: 273–278. [DOI] [PubMed] [Google Scholar]
  • 59. Zukin RS, Bennett MV (1995) Alternatively spliced isoforms of the NMDAR1 receptor subunit. Trends Neurosci 18:306–313. [DOI] [PubMed] [Google Scholar]
  • 60. Zupan V, Gonzalez P, Lacaze‐Masmonteil T, Boithias C, D'Allest AM, Dehan M, Gabilan JC (1996) Periventricular leukomalacia: Risk factors revisited. Dev Med Child Neurol 38: 1061–1067. [DOI] [PubMed] [Google Scholar]

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