Brain Structure and Function

, Volume 220, Issue 6, pp 3701–3720 | Cite as

Loss of lysophosphatidic acid receptor LPA1 alters oligodendrocyte differentiation and myelination in the mouse cerebral cortex

  • Beatriz García-Díaz
  • Raquel Riquelme
  • Isabel Varela-Nieto
  • Antonio Jesús Jiménez
  • Isabel de Diego
  • Ana lsabel Gómez-Conde
  • Elisa Matas-Rico
  • José Ángel Aguirre
  • Jerold Chun
  • Carmen Pedraza
  • Luis Javier Santín
  • Oscar Fernández
  • Fernando Rodríguez de Fonseca
  • Guillermo Estivill-TorrúsEmail author
Original Article


Lysophosphatidic acid (LPA) is an intercellular signaling lipid that regulates multiple cellular functions, acting through specific G-protein coupled receptors (LPA1–6). Our previous studies using viable Malaga variant maLPA1-null mice demonstrated the requirement of the LPA1 receptor for normal proliferation, differentiation, and survival of the neuronal precursors. In the cerebral cortex LPA1 is expressed extensively in differentiating oligodendrocytes, in parallel with myelination. Although exogenous LPA-induced effects have been investigated in myelinating cells, the in vivo contribution of LPA1 to normal myelination remains to be demonstrated. This study identified a relevant in vivo role for LPA1 as a regulator of cortical myelination. Immunochemical analysis in adult maLPA1-null mice demonstrated a reduction in the steady-state levels of the myelin proteins MBP, PLP/DM20, and CNPase in the cerebral cortex. The myelin defects were confirmed using magnetic resonance spectroscopy and electron microscopy. Stereological analysis limited the defects to adult differentiating oligodendrocytes, without variation in the NG2+ precursor cells. Finally, a possible mechanism involving oligodendrocyte survival was demonstrated by the impaired intracellular transport of the PLP/DM20 myelin protein which was accompanied by cellular loss, suggesting stress-induced apoptosis. These findings describe a previously uncharacterized in vivo functional role for LPA1 in the regulation of oligodendrocyte differentiation and myelination in the CNS, underlining the importance of the maLPA1-null mouse as a model for the study of demyelinating diseases.


Lysophosphatidic acid receptor Myelin Oligodendrocyte Cerebral cortex 



This work was supported by the Carlos III Health Institute, State Department of Research, Development and Innovation, Spanish Ministry of Economy and Competitiveness (Grant Numbers PI10/02514—co-funded by European Research Development Fund—, to G.E-T.; SAF2011 to IV-N); Andalusian Regional Ministries of Health (Nicolás Monardes Programme, and Grants PI0187/2008, PI0232/2007 to G.E-T.) and of Economy, Innovation, Science and Employment (CTS643 and CTS433 research group grants to G.E-T. and F.R-DF., respectively); Ramon Areces Foundation (Ramon Areces Fellowship to B.G-D.); and the National Institutes of Health (USA) (Grant Numbers MH051699 and MH01723 to J.C.). We gratefully acknowledge IBIMA joint services, common support structures for research (ECAI) of General Services, Microscopy and Animal Experimentation, for management, immunohistology and maintenance of mice, respectively, as well as technical assistance. Likewise we are obliged to central microscopy facilities at Universidad de Málaga for confocal and electron microscopy. The authors declare that they have no conflict of interest.

Supplementary material

429_2014_885_MOESM1_ESM.pdf (134 kb)
Supplementary material 1 (PDF 134 kb)


  1. Allard J, Barron S, Diaz J, Lubetzki C, Zalc B, Schwartz JC, Sokoloff P (1998) A rat G protein-coupled receptor selectively expressed in myelin-forming cells. Eur J Neurosci 10:1045–1053PubMedCrossRefGoogle Scholar
  2. Anliker B, Chun J (2004) Lysophospholipid G protein-coupled receptors. J Biol Chem 279:20555–20558PubMedCrossRefGoogle Scholar
  3. Anliker B, Choi JW, Lin ME, Gardell SE, Rivera RR, Kennedy G, Chun J (2013) Lysophosphatidic acid (LPA) and its receptor, LPA1, influence embryonic schwann cell migration, myelination, and cell-to-axon segregation. Glia 61:2009–2022PubMedCentralPubMedCrossRefGoogle Scholar
  4. Baslow MH (2003) N-Acetylaspartate in the vertebrate brain: metabolism and function. Neurochem Res 28:941–953PubMedCrossRefGoogle Scholar
  5. Baumann N, Pham-Dinh D (2001) Biology of oligodendrocyte and myelin in the mammalian central nervous system. Physiol Rev 81:871–927PubMedGoogle Scholar
  6. Bhakoo KK, Pearce D (2000) In vitro expression of N-acetyl aspartate by oligodendrocytes: implications for proton magnetic resonance spectroscopy signal in vivo. J Neurochem 74:254–262PubMedCrossRefGoogle Scholar
  7. Birgbauer E, Chun J (2006) New developments in the biological functions of lysophospholipids. Cell Mol Life Sci 63:2695–2701PubMedCrossRefGoogle Scholar
  8. Blanco E, Bilbao A, Luque MJ, Palomino A, Bermudez-Silva FJ, Suarez J, Santin L, Gutierrez A, Campos-Sandoval JA, Marquez J, Estivill-Torrus G, Rodriguez De Fonseca F (2012) Lack of cocaine-induced conditioned locomotion is associated with altered expression of hippocampal glutamate receptors in mice lacking lpa1 receptor. Psychopharmacology 220:27–42PubMedCrossRefGoogle Scholar
  9. Bonavita S, Di Salle F, Tedeschi G (1999) Proton MRS in neurological disorders. Eur J Radiol 30:125–131PubMedCrossRefGoogle Scholar
  10. Brinkmann V, Lynch KR (2002) FTY720: Targeting G-protein-coupled receptors for sphingosine 1-phosphate in transplantation and autoimmunity. Curr Opin Immunol 14:569–575PubMedCrossRefGoogle Scholar
  11. Castilla-Ortega E, Sánchez-López J, Hoyo-Becerra C, Matas Rico E, Zambrana-Infantes E, Chun J, Rodríguez de Fonseca F, Pedraza C, Estivill-Torrús G, Santín LJ (2010) Activity, anxiety and spatial memory impairments are dissociated in mice lacking the LPA1 receptor. Neurobiol Learn Mem 94:73–82PubMedCentralPubMedCrossRefGoogle Scholar
  12. Castilla-Ortega E, Hoyo-Becerra C, Pedraza C, Chun J, Rodríguez de Fonseca F, Estivill-Torrús G, Santín LJ (2011) Aggravation of the pathological consequences of chronic stress on hippocampal neurogenesis and spatial memory in mice lacking the LPA1 receptor. PLoS ONE 6(9):e25522PubMedCentralPubMedCrossRefGoogle Scholar
  13. Castilla-Ortega E, Pedraza C, Chun J, Rodríguez de Fonseca F, Estivill-Torrús G, Santin LJ (2012) Hippocampal c-Fos activation in normal and LPA1-null mice after two object recognition tasks with different memory demands. Behav Brain Res 232:400–405PubMedCrossRefGoogle Scholar
  14. Cervera P, Tirard M, Barron S, Allard J, Trottier S, Lacombe J, Daumas-Duport C, Sokoloff P (2002) Immunohistological localization of the myelinating cell-specific receptor LP(A1). Glia 38:126–136PubMedCrossRefGoogle Scholar
  15. Choi JW, Chun J (2013) Lysophospholipids and their receptors in the central nervous system. Biochim Biophys Acta 1831:20–32PubMedCentralPubMedCrossRefGoogle Scholar
  16. Choi JW, Herr DR, Noguchi K, Yung YC, Lee CW, Mutoh T, Lin ME, Teo ST, Park KE, Mosley AN, Chun J (2010) LPA receptors: subtypes and biological actions. Annu Rev Pharmacol Toxicol 50:157–186PubMedCrossRefGoogle Scholar
  17. Chun J (2005) Lysophospholipids in the nervous system. Prostaglandins Other Lipid Mediat 77:46–51PubMedCrossRefGoogle Scholar
  18. Chun J, Rosen H (2006) Lysophospholipid receptors as potential drug targets in tissue transplantation and autoimmune diseases. Curr Pharm Des 12:161–171PubMedCrossRefGoogle Scholar
  19. Colman DR, Kreibich G, Frey AB, Sabatini DD (1982) Synthesis and incorporation of myelin polypeptides into CNS myelin. J Cell Biol 95:598–608PubMedCrossRefGoogle Scholar
  20. Contos JJ, Fukushima N, Weiner JA, Kaushal D, Chun J (2000) Requirement for the lpA1 lysophosphatidic acid receptor gene in normal suckling behavior. Proc Natl Acad Sci USA 97:13384–13389PubMedCentralPubMedCrossRefGoogle Scholar
  21. Dawson J, Hotchin N, Lax S, Rumsby M (2003) Lysophosphatidic acid induces process retraction in CG-4 line oligodendrocytes and oligodendrocyte precursor cells but not in differentiated oligodendrocytes. J Neurochem 87:947–957PubMedCrossRefGoogle Scholar
  22. Dennis D, White MA, Forrest AD, Yuelling LM, Nogaroli L, Afshari FS, Fox MA, Fuss B (2008) Phosphodiesterase- I/Autotaxin’s MORFO domain regulates oligodendroglial process network formation and focal adhesion organization. Mol Cell Neurosci 37:412–424PubMedCentralPubMedCrossRefGoogle Scholar
  23. Dimou L, Simon C, Kirchhoff F, Takebayashi H, Götz M (2008) Progeny of Olig2-expressing progenitors in the gray and white matter of the adult mouse cerebral cortex. J Neurosci 28:10434–10442PubMedCrossRefGoogle Scholar
  24. Drøjdahl N, Nielsen HH, Gardi JE, Wree A, Peterson AC, Nyengaard JR, Eyer J, Finsen B (2010) Axonal plasticity elicits long-term changes in oligodendroglia and myelinated fibers. Glia 58:29–42PubMedCrossRefGoogle Scholar
  25. Edgar JM, Nave KA (2009) The role of CNS glia in preserving axon function. Curr Opin Neurobiol 19:498–504PubMedCrossRefGoogle Scholar
  26. Edgar JM, McLaughlin M, Werner HB, McCulloch MC, Barrie JA, Brown A, Faichney AB, Snaidero N, Nave KA, Griffiths IR (2009) Early ultrastructural defects of axons and axon-glia junctions in mice lacking expression of Cnp1. Glia 16:1815–1824CrossRefGoogle Scholar
  27. Emery B (2010) Regulation of oligodendrocyte differentiation and myelination. Science 330:779–782PubMedCrossRefGoogle Scholar
  28. Estivill-Torrús G, Llebrez-Zayas P, Matas-Rico E, Santín L, Pedraza C, De Diego I, Del Arco I, Fernández-Llebrez P, Chun J, Rodríguez de Fonseca F (2008) Absence of LPA1 signaling results in defective cortical development. Cereb Cortex 18:938–950PubMedCrossRefGoogle Scholar
  29. Estivill-Torrús G, Santín LJ, Pedraza C, Castilla-Ortega E, Rodriguez de Fonseca F (2013) Role of lysophosphatidic acid (LPA) in behavioral processes: implications for psychiatric disorders. In: Chun J (ed) Lysophospholipid receptors: signaling and biochemistry. Wiley, New Jersey, pp 451–474CrossRefGoogle Scholar
  30. Fannon AM, Moscarello MA (1990) Myelin basic protein is affected by reduced synthesis of myelin proteolipid protein in the jimpy mouse. Biochem J 268:105–110PubMedCentralPubMedCrossRefGoogle Scholar
  31. Filippi CG, Uluğ AM, Deck MD, Zimmerman RD, Heier LA (2002) Developmental delay in children: assessment with proton MR spectroscopy. Am J Neuroradiol 23:882–888PubMedGoogle Scholar
  32. Fox MA, Colello RJ, Macklin WB, Fuss B (2003) Phosphodiesterase-Ialpha/autotaxin: a counteradhesive protein expressed by oligodendrocytes during onset of myelination. Mol Cell Neurosci 23:507–519PubMedCrossRefGoogle Scholar
  33. García-Fernández M, Castilla-Ortega E, Pedraza C, Blanco E, Hurtado-Guerrero I, Barbancho MA, Chun J, Rodríguez-de-Fonseca F, Estivill-Torrús G, Santín Núñez LJ (2012) Chronic immobilization in the malpar1 knockout mice increases oxidative stress in the hippocampus. Int J Neurosci 122:583–589PubMedCrossRefGoogle Scholar
  34. Gow A, Southwood CM, Lazzarini RA (1998) Disrupted proteolipid protein trafficking results in oligodendrocyte apoptosis in an animal model of Pelizaeus–Merzbacher disease. J Cell Biol 140:925–934PubMedCentralPubMedCrossRefGoogle Scholar
  35. Griffiths I, Klugmann M, Anderson T, Yool D, Thomson C, Schwab MH, Schneider A, Zimmermann F, McCulloch M, Nadon N, Nave KA (1998) Axonal swellings and degeneration in mice lacking the major proteolipid of myelin. Science 280:1610–1613PubMedCrossRefGoogle Scholar
  36. Gundersen HJ, Bagger P, Bendtsen TF, Evans SM, Korbo L, Marcussen N, Moller A, Nielsen K, Nyengaard JR, Pakkenberg B, Sorensen FB, Vesterby A, West MJ (1988) The new stereological tools: dissector, fractionator, nucleator and point sampled intercepts and their use in pathological research and diagnosis. Acta Pathol Microbiol Immunol Scand 96:857–881CrossRefGoogle Scholar
  37. Hamilton BA, Yu BD (2012) Modifier genes and the plasticity of genetic networks in mice. PLoS Genet 8(4):e1002644PubMedCentralPubMedCrossRefGoogle Scholar
  38. Hammack BN, Fung KY, Hunsucker SW, Duncan MW, Burgoon MP, Owens GP, Gilden DH (2004) Proteomic analysis of multiple sclerosis cerebrospinal fluid. Mult Scler 10:245–260PubMedCrossRefGoogle Scholar
  39. Handford EJ, Smith D, Hewson L, McAllister G, Beer MS (2001) Edg2 receptor distribution in adult rat brain. Neuroreport 12:757–760PubMedCrossRefGoogle Scholar
  40. Ishibashi T, Dakin KA, Stevens B, Lee PR, Kozlov SV, Stewart CL, Fields RD (2006) Astrocytes promote myelination in response to electrical impulses. Neuron 49:823–832PubMedCentralPubMedCrossRefGoogle Scholar
  41. Ishii A, Fyffe-Maricich SL, Furusho M, Miller RH, Bansal R (2012) ERK1/ERK2 MAPK signaling is required to increase myelin thickness independent of oligodendrocyte differentiation and initiation of myelination. J Neurosci 32:8855–8864PubMedCentralPubMedCrossRefGoogle Scholar
  42. Kang SH, Fukaya M, Yang JK, Rothstein JD, Bergles DE (2010) NG2+ CNS glial progenitors remain committed to the oligodendrocyte lineage in postnatal life and following neurodegeneration. Neuron 68: 668–681Google Scholar
  43. Karim SA, Barrie JA, McCulloch MC, Montague P, Edgar JM, Kirkham D, Anderson TJ, Nave KA, Griffiths IR, McLaughlin M (2007) PLP overexpression perturbs myelin protein composition and myelination in a mouse model of Pelizaeus–Merzbacher disease. Glia 55:341–351PubMedCrossRefGoogle Scholar
  44. Kearney JA (2011) Genetic modifiers of neurological disease. Curr Opin Genet Dev 21:349–353PubMedCentralPubMedCrossRefGoogle Scholar
  45. Keshavan MS, Diwadkar VA, Harenski K, Rosenberg DR, Sweeney JA, Pettegrew JW (2002) Abnormalities of the corpus callosum in first episode, treatment naive schizophrenia. J Neurol Neurosurg Psychiatry 72:757–760PubMedCentralPubMedCrossRefGoogle Scholar
  46. Khiat A, Lesage J, Boulanger Y (2007) Quantitative MRS study of Baló’s concentric sclerosis lesions. Magn Reson Imaging 25:1112–1115PubMedCrossRefGoogle Scholar
  47. Klugmann M, Schwab MH, Pühlhofer A, Schneider A, Zimmermann F, Griffiths IR, Nave KA (1997) Assembly of CNS myelin in the absence of proteolipid protein. Neuron 18:59–70PubMedCrossRefGoogle Scholar
  48. Lin W, Popko B (2009) Endoplasmic reticulum stress in disorders of myelinating cells. Nat Neurosci 212:379–385CrossRefGoogle Scholar
  49. Lin ME, Herr DR, Chun J (2010) Lysophosphatidic acid (LPA) receptors: signaling properties and disease relevance. Prostaglandins Other Lipid Mediat 91:130–138PubMedCentralPubMedCrossRefGoogle Scholar
  50. Linstedt AD, Mehta A, Suhan J, Reggio H, Hauri HP (1997) Sequence and overexpression of GPP130/GIMPc: evidence for saturable pH-sensitive targeting of a type II early Golgi membrane protein. Mol Biol Cell 8:1073–1087PubMedCentralPubMedCrossRefGoogle Scholar
  51. Ma L, Hasan KM, Steinberg JL, Narayana PA, Lane SD, Zuniga EA, Kramer LA, Moeller FG (2009) Diffusion tensor imaging in cocaine dependence: regional effects of cocaine on corpus callosum and effect of cocaine administration route. Drug Alcohol Depend 104:262–267PubMedCentralPubMedCrossRefGoogle Scholar
  52. Matas-Rico E, García-Díaz B, Llebrez-Zayas P, López-Barroso D, Santín L, Pedraza C, Fernández-Llebrez P, Téllez T, Redondo M, Chun J, Rodríguez de Fonseca F, Estivill-Torrús G (2008) Deletion of lysophosphatidic acid receptor LPA1 reduces neurogenesis in the mouse dentate gyrus. Mol Cell Neurosci 39:342–355PubMedCentralPubMedCrossRefGoogle Scholar
  53. Matsushita T, Amagai Y, Soga T, Terai K, Obinata M, Hashimoto S (2005) A novel oligodendrocyte cell line OLP6 shows the successive stages of oligodendrocyte development: late progenitor, immature and mature stages. Neuroscience 136:115–121PubMedCrossRefGoogle Scholar
  54. McLaughlin M, Barrie JA, Karim SA, Montague P, Edgar JM, Kirkham D, Thomson CE, Griffiths IR (2006a) Processing of PLP in a model of Pelizaeus–Merzbacher disease/SPG2 due to the rumpshaker mutation. Glia 53:715–722PubMedCrossRefGoogle Scholar
  55. McLaughlin M, Karim SA, Montague P, Barrie JA, Kirkham D, Griffiths IR, Edgar JM (2006b) Genetic background influences UPR but not PLP processing in the rumpshaker model of PMD/SPG2. Neurochem Res 32:167–176PubMedCrossRefGoogle Scholar
  56. McLean IW, Nakane PK (1974) Periodate-lysine-paraformaldehyde fixative. A new fixative for immunoelectronmicroscopy. Histochem Cytochem 22:1077CrossRefGoogle Scholar
  57. Miller DH, Austin SJ, Connelly A, Youl BD, Gadian DG, McDonald WI (1991) Proton magnetic resonance spectroscopy of an acute and chronic lesion in multiple sclerosis. Lancet 337:58–59PubMedCrossRefGoogle Scholar
  58. Miyata S, Koyama Y, Takemoto K, Yoshikawa K, Ishikawa T, Taniguchi M, Inoue K, Aoki M, Hori O, Katayama T, Tohyama M (2011) Plasma corticosterone activates SGK1 and induces morphological changes in oligodendrocytes in corpus callosum. PLoS ONE 6:e19859PubMedCentralPubMedCrossRefGoogle Scholar
  59. Möller T, Musante DB, Ransom BR (1999) Lysophosphatidic acid-induced calcium signals in cultured rat oligodendrocytes. NeuroReport 10:2929–2932PubMedCrossRefGoogle Scholar
  60. Monge M, Kadiiski D, Jacque CM, Zalc B (1986) Oligodendroglial expression and deposition of four major myelin constituents in the myelin sheath during development. An in vivo study. Dev Neurosci 8:222–235PubMedCrossRefGoogle Scholar
  61. Moolenar WH, van Meeteren LA, Giepmans BNG (2004) The ins and outs of lysophosphatidic acid signaling. BioEssays 26:870–881CrossRefGoogle Scholar
  62. Moore CS, Milner R, Nishiyama A, Frausto RF, Serwanski DR, Pagarigan RR, Whitton JL, Miller RH, Crocker SJ (2011) Astrocytic tissue inhibitor of metalloproteinase-1 (TIMP-1) promotes oligodendrocyte differentiation and enhances CNS myelination. J Neurosci 31:6247–6254PubMedCentralPubMedCrossRefGoogle Scholar
  63. Nakahara J, Tan-Takeuchi K, Seiwa C, Yagi T, Aiso S, Kawamura K, Asou H (2001) Myelin basic protein is necessary for the regulation of myelin-associated glycoprotein expression in mouse oligodendroglia. Neurosci Lett 298:163–166PubMedCrossRefGoogle Scholar
  64. Narayana PA, Ahobila-Vajjula P, Ramu J, Herrera J, Steinberg JL, Moeller FG (2009) Diffusion tensor imaging of cocaine-treated rodents. Psychiatry Res 171:242–251PubMedCentralPubMedCrossRefGoogle Scholar
  65. Nave KA (2010) Myelination and support of axonal integrity by glia. Nature 468:244–252PubMedCrossRefGoogle Scholar
  66. Nogaroli L, Yuelling LM, Dennis J, Gorse K, Payne SG, Fuss B (2009) Lysophosphatidic acid can support the formation of membranous structures and an increase in MBP mRNA levels in differentiating oligodendrocytes. Neurochem Res 34:182–193PubMedCentralPubMedCrossRefGoogle Scholar
  67. Noguchi K, Herr D, Mutoh T, Chun J (2009) Lysophosphatidic acid (LPA) and its receptors. Curr Opin Pharmacol 9:15–23PubMedCrossRefGoogle Scholar
  68. Norton WT, Poduslo SE (1973) Myelination in rat brain: method of myelin isolation. J Neurochem 21:749–757PubMedCrossRefGoogle Scholar
  69. Paxinos G, Franklin KBJ (2001) The mouse brain in stereotaxic coordinates. Academic Press, San DiegoGoogle Scholar
  70. Pedraza C, Sánchez-López J, Castilla-Ortega E, Rosell-Valle C, Zambrana-Infantes E, García-Fernández M, Rodriguez de Fonseca F, Chun J, Santín LJ, Estivill-Torrús G (2013) Fear extinction and acute stress reactivity reveal a role of LPA1 receptor in regulating emotional-like behaviors. Brain Struct Funct. doi: 10.1007/s00429-013-0592-9 PubMedGoogle Scholar
  71. Penet MF, Laigle C, Fur YL, Confort-Gouny S, Heurteaux C, Cozzone PJ, Viola A (2006) In vivo characterization of brain morphometric and metabolic endophenotypes in three inbred strains of mice using magnetic resonance techniques. Behav Genet 36:732–744PubMedCrossRefGoogle Scholar
  72. Peters A, Palay SL, Webster HD (1991) The fine structure of the nervous system: neurons and their supporting cells. Oxford University Press, New YorkGoogle Scholar
  73. Rivers LE, Young KM, Rizzi M, Jamen F, Psachoulia K, Wade A, Kessaris N, Richardson WD (2008) PDGFRA/NG2 glia generate myelinating oligodendrocytes and piriform projection neurons in adult mice. Nat Neurosci 11:1392–1401PubMedCrossRefGoogle Scholar
  74. Roberts C, Winter P, Shilliam CS, Hughes ZA, Langmead C, Maycox PR, Dawson LA (2005) Neurochemical changes in LPA1 receptor deficient mice-a putative model of schizophrenia. Neurochem Res 30:371–377PubMedCrossRefGoogle Scholar
  75. Rohrer J, Schweizer A, Russell D, Kornfeld S (1996) The targeting of Lamp1 to lysosomes is dependent on the spacing of its cytoplasmic tail tyrosine sorting motif relative to the membrane. J Cell Biol 132:565–576PubMedCrossRefGoogle Scholar
  76. Rosenbluth J, Nave KA, Mierzwa A, Schiff R (2006) Subtle myelin defects in PLP-null mice. Glia 54:172–182PubMedCrossRefGoogle Scholar
  77. Santín L, Bilbao A, Pedraza C, Matas-Rico E, López-Barroso D, Castilla-Ortega E, Sánchez-López J, Riquelme R, Varela-Nieto I, De la Villa P, Suardiaz M, Chun J, Rodríguez de Fonseca F, Estivill-Torrús G (2009) Behavioral phenotype of maLPA1-null mice: increased anxiety-like behavior and spatial memory deficits. Genes Brain Behav 8:772–784PubMedCrossRefGoogle Scholar
  78. Sherman DL, Brophy PJ (2005) Mechanisms of axon ensheathment and myelin growth. Nat Rev Neurosci 6:683–690PubMedCrossRefGoogle Scholar
  79. Simone IL, Federico F, Trojano M, Tortorella C, Liguori M, Giannini P, Picciola E, Natile G, Livrea P (1996) High resolution proton MR spectroscopy of cerebrospinal fluid in MS patients. Comparison with biochemical changes in demyelinating plaques. J Neurol Sci 144:182–190PubMedCrossRefGoogle Scholar
  80. Sohn J, Selvaraj V, Wakayama K, Orosco L, Lee E, Crawford SE, Guo F, Lang J, Horiuchi M, Zarbalis K, Itoh T, Deng W, Pleasure D (2012) PEDF is a novel oligodendrogenic morphogen acting on the adult SVZ and corpus callosum. J Neurosci 32:12152–12164PubMedCentralPubMedCrossRefGoogle Scholar
  81. Somogyi P, Takagi H (1982) A note on the use of picric acid–paraformaldehyde–glutaraldehyde fixative for correlated light- and electron microscopic immunocytochemistry. Neuroscience 7:1779PubMedCrossRefGoogle Scholar
  82. Sorensen A, Moffat K, Thomson C, Barnett SC (2008) Astrocytes, but not olfactory ensheathing cells or Schwann cells, promote myelination of CNS axons in vitro. Glia 56:750–763PubMedCrossRefGoogle Scholar
  83. Southwood C, Gow A (2001) Molecular pathways of oligodendrocyte apoptosis revealed by mutations in the proteolipid protein gene. Microsc Res Tech 52:700–708PubMedCrossRefGoogle Scholar
  84. Southwood CM, Garbern J, Jiang W, Gow A (2002) The unfolded protein response modulates disease severity in Pelizaeus–Merzbacher disease. Neuron 36:585–596PubMedPubMedCentralCrossRefGoogle Scholar
  85. Spohr TC, Choi JW, Gardell SE, Herr DR, Rehen SK, Gomes FC, Chun J (2008) Lysophosphatidic acid receptor-dependent secondary effects via astrocytes promote neuronal differentiation. J Biol Chem 283:7470–7479PubMedCrossRefGoogle Scholar
  86. Spohr TC, Dezonne RS, Rehen SK, Gomes FC (2011) Astrocytes treated by lysophosphatidic acid induce axonal outgrowth of cortical progenitors through extracellular matrix protein and epidermal growth factor signaling pathway. J Neurochem 119:113–123CrossRefGoogle Scholar
  87. Stankoff B, Barron S, Allard J, Barbin G, Noel F, Aigrot MS, Premont J, Sokoloff P, Zalc B, Lubetzki C (2002) Oligodendroglial expression of Edg-2 receptor: developmental analysis and pharmacological responses to lysophosphatidic acid. Mol Cell Neurosci 20:415–428PubMedCrossRefGoogle Scholar
  88. Steen RG, Ogg RJ (2005) Abnormally high levels of brain N-acetylaspartate in children with sickle cell disease. Am J Neuroradiol 26:463–468PubMedGoogle Scholar
  89. Tigyi G (2010) Aiming drug discovery at lysophosphatidic acid targets. Br J Pharmacol 161:241–270PubMedCentralPubMedCrossRefGoogle Scholar
  90. Tkachev D, Mimmack ML, Ryan MM, Wayland M, Freeman T, Jones PB, Starkey M, Webster MJ, Yolken RH, Bahn S (2003) Oligodendrocyte dysfunction in schizophrenia and bipolar disorder. Lancet 362:798–804PubMedCrossRefGoogle Scholar
  91. Trapp BD, Moench M, Pulley E, Barbosa E, Tennekoon GI, Griffin J (1987) Spatial segregation of mRNA encoding myelinspecific proteins. Proc Natl Acad Sci USA 84:7773–7777PubMedCentralPubMedCrossRefGoogle Scholar
  92. Urenjak J, Williams SR, Gadian DG, Noble M (1992) Specific expression of N-acetylaspartate in neurons, oligodendrocyte-type-2 astrocyte progenitors, and immature oligodendrocytes in vitro. J Neurochem 59:55–61PubMedCrossRefGoogle Scholar
  93. Van der Knaap LJ, van der Ham IJ (2011) How does the corpus callosum mediate interhemispheric transfer? A review. Behav Brain Res 223:211–221PubMedCrossRefGoogle Scholar
  94. Villarreal G, Hamilton DA, Graham DP, Driscoll I, Qualls C, Petropoulos H, Brooks WM (2004) Reduced area of the corpus callosum in posttraumatic stress disorder. Psychiatry Res 131:227–235PubMedCrossRefGoogle Scholar
  95. Wang CC (1998) Protein disulfide isomerase assists protein folding as both an isomerase and a chaperone. Ann N Y Acad Sci 864:9–13PubMedCrossRefGoogle Scholar
  96. Warringa RAJ, Hoeben RC, Koper JW, Sykes JEC, van Golde LMG, Lopes-Cardozo M (1987) Hydrocortisone stimulates the development of oligodendrocytes in primary glial cultures and affects glucose metabolism and lipid synthesis in these cultures. Dev Br Res 34:79–86CrossRefGoogle Scholar
  97. Watkins TA, Emery B, Mulinyawe S, Barres BA (2008) Distinct stages of myelination regulated by gamma-secretase and astrocytes in a rapidly myelinating CNS coculture system. Neuron 60:555–569PubMedCentralPubMedCrossRefGoogle Scholar
  98. Weiner JA, Hecht JH, Chun J (1998) Lysophosphatidic acid receptor gene vzg-1/lpA1/edg-2 is expressed by mature oligodendrocytes during myelination in the postnatal murine brain. J Comp Neurol 398:587–598PubMedCrossRefGoogle Scholar
  99. Werner HB, Kuhlmann K, Shen S, Uecker M, Schardt A, Dimova K, Orfaniotou F, Dhaunchak A, Brinkmann BG, Möbius W, Guarente L, Casaccia-Bonnefil P, Jahn O, Nave KA (2007) Proteolipid protein is required for transport of sirtuin 2 into CNS myelin. J Neurosci 27:7717–7730PubMedCentralPubMedCrossRefGoogle Scholar
  100. West MJ (1993) New stereological methods for counting neurons. Neurobiol Aging 14:275–285PubMedCrossRefGoogle Scholar
  101. Whitford TJ, Kubicki M, Schneiderman JS, O’Donnell LJ, King R, Alvarado JL, Khan U, Markant D, Nestor PG, Niznikiewicz M, McCarley RW, Westin CF, Shenton ME (2010) Corpus callosum abnormalities and their association with psychotic symptoms in patients with schizophrenia. Biol Psychiatry 68:70–77PubMedCentralPubMedCrossRefGoogle Scholar
  102. Yu N, Lariosa-Willingham KD, Lin FF, Webb M, Rao TS (2004) Characterization of lysophosphatidic acid and sphingosine-1-phosphate-mediated signal transduction in rat cortical oligodendrocytes. Glia 45:17–27PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Beatriz García-Díaz
    • 1
    • 2
  • Raquel Riquelme
    • 3
  • Isabel Varela-Nieto
    • 3
  • Antonio Jesús Jiménez
    • 4
  • Isabel de Diego
    • 5
  • Ana lsabel Gómez-Conde
    • 6
  • Elisa Matas-Rico
    • 1
    • 7
  • José Ángel Aguirre
    • 8
  • Jerold Chun
    • 9
  • Carmen Pedraza
    • 10
  • Luis Javier Santín
    • 10
  • Oscar Fernández
    • 11
  • Fernando Rodríguez de Fonseca
    • 12
  • Guillermo Estivill-Torrús
    • 1
    • 6
    Email author
  1. 1.Laboratorio de Investigación, UGC Intercentros de Neurociencias, Instituto de Investigación Biomédica de Málaga (IBIMA)Hospitales Universitarios Regional de Málaga y Virgen de la Victoria, Hospital CivilMálagaSpain
  2. 2.Department of Neurology, H. Houston Merritt Clinical Research CenterColumbia University Medical CenterNew YorkUSA
  3. 3.Instituto de Investigaciones Biomédicas ‘Alberto Sols’, Consejo Superior de Investigaciones Científicas (CSIC)Universidad Autónoma de Madrid (UAM)MadridSpain
  4. 4.Departamento de Biología Celular, Genética y Fisiología, Instituto de Investigación Biomédica de Málaga (IBIMA)Universidad de MálagaMálagaSpain
  5. 5.Departamento de Anatomía y Medicina LegalUniversidad de MálagaMálagaSpain
  6. 6.ECAI de Microscopía, Instituto de Investigación Biomédica de Málaga (IBIMA)Hospitales Universitarios Regional de Málaga y Virgen de la VictoriaMálagaSpain
  7. 7.Division of Cell Biology IThe Netherlands Cancer InstituteAmsterdamThe Netherlands
  8. 8.Departamento de Fisiología Humana y Educación Físico DeportivaUniversidad de MálagaMálagaSpain
  9. 9.Department of Molecular and Cellular Neuroscience, Dorris Neuroscience CentreThe Scripps Research InstituteLa JollaUSA
  10. 10.Departamento de Psicobiología y Metodología de las Ciencias del Comportamiento, Instituto de Investigación Biomédica de Málaga (IBIMA)Universidad de MálagaMálagaSpain
  11. 11.Neurology Service, UGC Intercentros de Neurociencias, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospitales Universitarios Regional de Málaga y Virgen de la VictoriaUniversidad de MálagaMálagaSpain
  12. 12.Laboratorio de Medicina Regenerativa, UGC de Salud Mental, Instituto de Investigación Biomédica de Málaga (IBIMA)Hospital Universitario Regional de MálagaMálagaSpain

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