Neurochemical Research

, Volume 32, Issue 2, pp 363–376

Genetic Program of Neuronal Differentiation and Growth Induced by Specific Activation of NMDA Receptors

  • Cristina A. Ghiani
  • Luis Beltran-Parrazal
  • Daniel M. Sforza
  • Jemily S. Malvar
  • Akop Seksenyan
  • Ruth Cole
  • Desmond J. Smith
  • Andrew Charles
  • Pedro A. Ferchmin
  • Jean de Vellis
Original Paper

Abstract

Glutamate and its receptors are expressed very early during development and may play important roles in neurogenesis, synapse formation and brain wiring. The levels of glutamate and activity of its receptors can be influenced by exogenous factors, leading to neurodevelopmental disorders. To investigate the role of NMDA receptors on gene regulation in a neuronal model, we used primary neuronal cultures developed from embryonic rat cerebri in serum-free medium. Using Affymetrix Gene Arrays, we found that genes known to be involved in neuronal plasticity were differentially expressed 24 h after a brief activation of NMDA receptors. The upregulation of these genes was accompanied by a sustained induction of CREB phosphorylation, and an increase in synaptophysin immunoreactivity. We conclude that NMDA receptor activation elicits expression of genes whose downstream products are involved in the regulation of early phases of the process leading to synaptogenesis and its consolidation, at least in part through sustained CREB phosphorylation.

Keywords

N-methyl-D-Aspartate Cortical neurons DNA array Gene regulation CREB Brain development 

Abbreviations

NMDA

N-methyl-d-aspartate

AMPA

α-Amino-3-hydroxy-5-methylisoxazole-4-propionic acid

BDNF

Brain derived neurotrophic factor

CREB

cAMP responsive element binding

CBP

CREB binding protein

IEGs

Immediate early genes

LTP

Long term potentiation

NARP

Neuronal activity-regulated pentraxin

NF-L

Light molecular-weight neurofilament

NGFI-B

NGF-induced factor B

NOR

Neuron-derived orphan receptor

pCREB

Phosphorylated CREB

References

  1. 1.
    Hagberg H, Mallard C (2000) Antenatal brain injury: aetiology and possibilities of prevention. Semin Neonatol 5(1):41–51PubMedCrossRefGoogle Scholar
  2. 2.
    Rees S, Inder T (2005) Fetal and neonatal origins of altered brain development. Early Human Dev 81(9):753–761CrossRefGoogle Scholar
  3. 3.
    Johnston MV (2004) Clinical disorders of brain plasticity. Brain Dev 26(2):73–80PubMedCrossRefGoogle Scholar
  4. 4.
    Johnston MV (2005) Excitotoxicity in perinatal brain injury. Brain Pathol 15(3):234–240PubMedCrossRefGoogle Scholar
  5. 5.
    Nguyen L, Rigo JM, Rocher V et al (2001) Neurotransmitters as early signals for central nervous system development. Cell Tissue Res 305(2):187–202PubMedCrossRefGoogle Scholar
  6. 6.
    Cameron HA, Hazel TG, McKay RD (1998) Regulation of neurogenesis by growth factors and neurotransmitters. J Neurobiol 36(2):287–306PubMedCrossRefGoogle Scholar
  7. 7.
    Herlenius E, Lagercrantz H (2004) Development of neurotransmitter systems during critical periods. Exp Neurol 190(Suppl 1):S8–S21PubMedCrossRefGoogle Scholar
  8. 8.
    Kew JN, Kemp JA (2005) Ionotropic and metabotropic glutamate receptor structure and pharmacology. Psychopharmacology (Berl). 179(1):4–29CrossRefGoogle Scholar
  9. 9.
    Dingledine R, Borges K, Bowie D et al (1999) The glutamate receptor ion channels. Pharmacol Rev 51(1):7–61PubMedGoogle Scholar
  10. 10.
    Lujan R, Shigemoto R, Lopez-Bendito G (2005) Glutamate and GABA receptor signalling in the developing brain. Neuroscience 130(3):567–580PubMedCrossRefGoogle Scholar
  11. 11.
    Komuro H, Rakic P (1998) Orchestration of neuronal migration by activity of ion channels, neurotransmitter receptors, and intracellular Ca2+ fluctuations. J Neurobiol 37(1):110–130PubMedCrossRefGoogle Scholar
  12. 12.
    Gould E, Cameron HA (1997) Early NMDA receptor blockade impairs defensive behavior and increases cell proliferation in the dentate gyrus of developing rats. Behav Neurosci. 111(1):49–56PubMedCrossRefGoogle Scholar
  13. 13.
    Ikonomidou C, Bosch F, Miksa M et al (1999) Blockade of NMDA receptors and apoptotic neurodegeneration in the developing brain. Science 283(5398):70–74PubMedCrossRefGoogle Scholar
  14. 14.
    Lipton SA, Nakanishi N (1999) Shakespeare in love—with NMDA receptors? Nat Med 5(3):270–271PubMedCrossRefGoogle Scholar
  15. 15.
    Sheng M, Kim MJ (2002) Postsynaptic signaling and plasticity mechanisms. Science. 298(5594):776–780PubMedCrossRefGoogle Scholar
  16. 16.
    Frey U, Morris RG (1997) Synaptic tagging and long-term potentiation. Nature 385(6616):533–536PubMedCrossRefGoogle Scholar
  17. 17.
    Kaufmann WE, Worley PF (1999) Neural activity and immediate early gene expression in the cerebral cortex. Mental Retardation Dev Disabilities Res Rev 5(1):41–50CrossRefGoogle Scholar
  18. 18.
    Nguyen PV, Kandel ER (1996) A macromolecular synthesis-dependent late phase of long-term potentiation requiring cAMP in the medial perforant pathway of rat hippocampal slices. J Neurosci 16(10):3189–3198PubMedGoogle Scholar
  19. 19.
    Otani S, Abraham WC (1989) Inhibition of protein synthesis in the dentate gyrus, but not the entorhinal cortex, blocks maintenance of long-term potentiation in rats. Neurosci Lett 106(1–2):175–180PubMedCrossRefGoogle Scholar
  20. 20.
    Steward O, Schuman EM (2001) Protein synthesis at synaptic sites on dendrites. Annu Rev Neurosci 24:299–325PubMedCrossRefGoogle Scholar
  21. 21.
    West AE, Griffith EC, Greenberg ME (2002) Regulation of transcription factors by neuronal activity. Nat Rev Neurosci 3(12):921–931PubMedCrossRefGoogle Scholar
  22. 22.
    Nedivi E, Hevroni D, Naot D et al (1993) Numerous candidate plasticity-related genes revealed by differential cDNA cloning. Nature 363(6431):718–722PubMedCrossRefGoogle Scholar
  23. 23.
    Qian Z, Gilbert ME, Colicos MA et al (1993) Tissue-plasminogen activator is induced as an immediate-early gene during seizure, kindling and long-term potentiation. Nature 361(6411):453–457PubMedCrossRefGoogle Scholar
  24. 24.
    French PJ, O’Connor V, Voss K et al (2001) Seizure-induced gene expression in area CA1 of the mouse hippocampus. Eur J Neurosci 14(12):2037–2041PubMedCrossRefGoogle Scholar
  25. 25.
    Sala C, Rudolph-Correia S, Sheng M (2000) Developmentally regulated NMDA receptor-dependent dephosphorylation of cAMP response element-binding protein (CREB) in hippocampal neurons. J Neurosci 20(10):3529–3536PubMedGoogle Scholar
  26. 26.
    Lanahan A, Worley P (1998) Immediate-early genes and synaptic function. Neurobiol Learn Mem 70(1–2):37–43PubMedCrossRefGoogle Scholar
  27. 27.
    Nesic O, Svrakic NM, Xu GY et al (2002) DNA microarray analysis of the contused spinal cord: effect of NMDA receptor inhibition. J Neurosci Res 68(4):406–423PubMedCrossRefGoogle Scholar
  28. 28.
    Ying G, Huang C, Jing N et al (2001) Identification of differentially expressed genes in the denervated rat hippocampus by cDNA arrays. Neurosci Lett 306(1–2):121–125PubMedCrossRefGoogle Scholar
  29. 29.
    Sugiura N, Patel RG, Corriveau RA (2001) N-methyl-d-aspartate receptors regulate a group of transiently expressed genes in the developing brain. J Biol Chem 276(17):14257–14263PubMedGoogle Scholar
  30. 30.
    Ghiani CA, Lelievre V, Beltran-Parrazal L et al (2006) Gene expression is differentially regulated by neurotransmitters in embryonic neuronal cortical culture. J Neurochem 97(Suppl 1):35–43PubMedCrossRefGoogle Scholar
  31. 31.
    Platenik J, Kuramoto N, Yoneda Y (2000) Molecular mechanisms associated with long-term consolidation of the NMDA signals. Life Sci 67(4):335–364PubMedCrossRefGoogle Scholar
  32. 32.
    Espinosa-Jeffrey A, Becker-Catania SG, Zhao PM et al (2002) Selective specification of CNS stem cells into oligodendroglial or neuronal cell lineage: cell culture and transplant studies. J Neurosci Res 69(6):810–825PubMedCrossRefGoogle Scholar
  33. 33.
    Irizarry RA, Hobbs B, Collin F et al (2003) Exploration, normalization, and summaries of high density oligonucleotide array probe level data. Biostatistics 4(2):249–264PubMedCrossRefGoogle Scholar
  34. 34.
    Tamayo P, Slonim D, Mesirov J et al (1999) Interpreting patterns of gene expression with self-organizing maps: methods and application to hematopoietic differentiation. Proc Natl Acad Sci USA 96(6):2907–2912PubMedCrossRefGoogle Scholar
  35. 35.
    Mathews DH, Sabina J, Zuker M et al (1999) Expanded sequence dependence of thermodynamic parameters improves prediction of RNA secondary structure. J Mol Biol 288(5):911–940PubMedCrossRefGoogle Scholar
  36. 36.
    Zuker M (2003) Mfold web server for nucleic acid folding and hybridization prediction. Nucleic Acids Res 31(13):3406–3415PubMedCrossRefGoogle Scholar
  37. 37.
    Ghiani CA, Eisen AM, Yuan X et al (1999) Neurotransmitter receptor activation triggers p27(Kip1 )and p21(CIP1) accumulation and G1 cell cycle arrest in oligodendrocyte progenitors. Development 126(5):1077–1090PubMedGoogle Scholar
  38. 38.
    Ghiani CA, Gallo V (2001) Inhibition of cyclin E-cyclin-dependent kinase 2 complex formation and activity is associated with cell cycle arrest and withdrawal in oligodendrocyte progenitor cells. J Neurosci 21(4):1274–1282PubMedGoogle Scholar
  39. 39.
    Alder J, Thakker-Varia S, Bangasser DA et al (2003) Brain-derived neurotrophic factor-induced gene expression reveals novel actions of VGF in hippocampal synaptic plasticity. J Neurosci 23(34):10800–10808PubMedGoogle Scholar
  40. 40.
    Ahn S, Riccio A,, Ginty DD (2000) Spatial considerations for stimulus-dependent transcription in neurons. Annu Rev Physiol 62:803–823PubMedCrossRefGoogle Scholar
  41. 41.
    Shaywitz AJ, Greenberg ME (1999) CREB: a stimulus-induced transcription factor activated by a diverse array of extracellular signals. Annu Rev Biochem 68:821–861PubMedCrossRefGoogle Scholar
  42. 42.
    Biranowska J, Dziewiatkowski J, Ludkiewicz B et al (2002) Developmental changes of synaptic proteins expression within the hippocampal formation of the rat. Anat Embryol (Berl) 206(1–2):85–96CrossRefGoogle Scholar
  43. 43.
    Knaus P, Betz H,, Rehm H (1986) Expression of synaptophysin during postnatal development of the mouse brain. J Neurochem 47(4):1302–1304PubMedCrossRefGoogle Scholar
  44. 44.
    Castro DS, Hermanson E, Joseph B et al (2001) Induction of cell cycle arrest and morphological differentiation by Nurr1 and retinoids in dopamine MN9D cells. J Biol Chem 276(46):43277–43284PubMedCrossRefGoogle Scholar
  45. 45.
    Maxwell MA, Muscat GE (2006) The NR4A subgroup: immediate early response genes with pleiotropic physiological roles. Nucl Recept Signal 4:e002PubMedCrossRefGoogle Scholar
  46. 46.
    Benoit G, Malewicz M, Perlmann T (2004) Digging deep into the pockets of orphan nuclear receptors: insights from structural studies. Trends Cell Biol 14(7):369–376PubMedCrossRefGoogle Scholar
  47. 47.
    Zetterstrom RH, Solomin L, Mitsiadis T et al (1996) Retinoid X receptor heterodimerization and developmental expression distinguish the orphan nuclear receptors NGFI-B, Nurr1, and Nor1. Mol Endocrinol 10(12):1656–1666PubMedCrossRefGoogle Scholar
  48. 48.
    Ponnio T, Conneely OM (2004) nor-1 regulates hippocampal axon guidance, pyramidal cell survival, and seizure susceptibility. Mol Cell Biol 24(20):9070–9078PubMedCrossRefGoogle Scholar
  49. 49.
    Bottai D, Guzowski JF, Schwarz MK et al (2002) Synaptic activity-induced conversion of intronic to exonic sequence in Homer 1 immediate early gene expression. J Neurosci 22(1):167–175PubMedGoogle Scholar
  50. 50.
    Brakeman PR, Lanahan AA, O’Brien R et al (1997) Homer: a protein that selectively binds metabotropic glutamate receptors. Nature 386(6622):284–288PubMedCrossRefGoogle Scholar
  51. 51.
    Kato A, Ozawa F, Saitoh Y et al (1997) vesl, a gene encoding VASP/Ena family related protein, is upregulated during seizure, long-term potentiation and synaptogenesis. FEBS Lett 412(1):183–189PubMedCrossRefGoogle Scholar
  52. 52.
    Sato M, Suzuki K, Nakanishi S (2001) NMDA receptor stimulation and brain-derived neurotrophic factor upregulate homer 1a mRNA via the mitogen-activated protein kinase cascade in cultured cerebellar granule cells. J Neurosci 21(11):3797–3805PubMedGoogle Scholar
  53. 53.
    Raghavendra Rao VL, Dhodda VK, Song G et al (2003) Traumatic brain injury-induced acute gene expression changes in rat cerebral cortex identified by GeneChip analysis. J Neurosci Res 71(2):208–219PubMedCrossRefGoogle Scholar
  54. 54.
    Ammon S, Mayer P, Riechert U et al (2003) Microarray analysis of genes expressed in the frontal cortex of rats chronically treated with morphine and after naloxone precipitated withdrawal. Brain Res Mol Brain Res 112(1–2):113–125PubMedCrossRefGoogle Scholar
  55. 55.
    Koya E, Spijker S, Voorn P et al (2006) Enhanced cortical and accumbal molecular reactivity associated with conditioned heroin, but not sucrose-seeking behaviour. J Neurochem 98(3):905–915PubMedCrossRefGoogle Scholar
  56. 56.
    de Bartolomeis A, Iasevoli F (2003) The Homer family and the signal transduction system at glutamatergic postsynaptic density: potential role in behavior and pharmacotherapy. Psychopharmacol Bull 37(3):51–83PubMedGoogle Scholar
  57. 57.
    Berke JD, Paletzki RF, Aronson GJ et al (1998) A complex program of striatal gene expression induced by dopaminergic stimulation. J Neurosci 18(14):5301–5310PubMedGoogle Scholar
  58. 58.
    Xiao B, Tu JC,, Worley PF (2000) Homer: a link between neural activity and glutamate receptor function. Curr Opin Neurobiol 10(3):370–374PubMedCrossRefGoogle Scholar
  59. 59.
    Szumlinski KK, Kalivas PW, Worley PF (2006) Homer proteins: implications for neuropsychiatric disorders. Curr Opin Neurobiol 16(3):251–257PubMedCrossRefGoogle Scholar
  60. 60.
    Herdegen T, Leah JD (1998) Inducible and constitutive transcription factors in the mammalian nervous system: control of gene expression by Jun, Fos, Krox, and CREB/ATF proteins. Brain Res Brain Res Rev 28(3):370–490PubMedCrossRefGoogle Scholar
  61. 61.
    Ammon-Treiber S, Hollt V (2005) Morphine-induced changes of gene expression in the brain. Addict Biol 10(1):81–89PubMedCrossRefGoogle Scholar
  62. 62.
    Chao MV (2003) Neurotrophins and their receptors: a convergence point for many signalling pathways. Nat Rev Neurosci 4(4):299–309PubMedCrossRefGoogle Scholar
  63. 63.
    Lee SH, Sheng M (2000) Development of neuron–neuron synapses. Curr Opin Neurobiol 10(1):125–131PubMedCrossRefGoogle Scholar
  64. 64.
    Pozzo-Miller LD, Gottschalk W, Zhang L et al (1999) Impairments in high-frequency transmission, synaptic vesicle docking, and synaptic protein distribution in the hippocampus of BDNF knockout mice. J Neurosci 19(12):4972–4983PubMedGoogle Scholar
  65. 65.
    Benson DL, Salton SR (1996) Expression and polarization of VGF in developing hippocampal neurons. Brain Res Dev Brain Res 96(1–2):219–228PubMedCrossRefGoogle Scholar
  66. 66.
    Trani E, Ciotti T, Rinaldi AM et al (1995) Tissue-specific processing of the neuroendocrine protein VGF. J Neurochem 65(6):2441–2449PubMedCrossRefGoogle Scholar
  67. 67.
    Snyder SE, Cheng HW, Murray KD et al (1998) The messenger RNA encoding VGF, a neuronal peptide precursor, is rapidly regulated in the rat central nervous system by neuronal activity, seizure and lesion. Neuroscience 82(1):7–19PubMedCrossRefGoogle Scholar
  68. 68.
    Salton SR, Ferri GL, Hahm S et al (2000) VGF: a novel role for this neuronal and neuroendocrine polypeptide in the regulation of energy balance. Front Neuroendocrinol 21(3):199–219PubMedCrossRefGoogle Scholar
  69. 69.
    Tsui CC, Copeland NG, Gilbert DJ et al (1996) NARP, a novel member of the pentraxin family, promotes neurite outgrowth and is dynamically regulated by neuronal activity. J Neurosci 16(8):2463–2478PubMedGoogle Scholar
  70. 70.
    Reti IM, Reddy R, Worley PF et al (2002) Prominent NARP expression in projection pathways and terminal fields. J Neurochem 82(4):935–944PubMedCrossRefGoogle Scholar
  71. 71.
    O’Brien RJ, Xu D, Petralia RS et al (1999) Synaptic clustering of AMPA receptors by the extracellular immediate-early gene product NARP. Neuron 23(2):309–323PubMedCrossRefGoogle Scholar
  72. 72.
    Lonze BE, Ginty DD (2002) Function and regulation of CREB family transcription factors in the nervous system. Neuron 35(4):605–623PubMedCrossRefGoogle Scholar
  73. 73.
    Dawson TM, Ginty DD (2002) CREB family transcription factors inhibit neuronal suicide. Nat Med 8(5):450–451PubMedCrossRefGoogle Scholar
  74. 74.
    Mantamadiotis T, Lemberger T, Bleckmann SC et al (2002) Disruption of CREB function in brain leads to neurodegeneration. Nat Genet 31(1):47–54PubMedCrossRefGoogle Scholar
  75. 75.
    Daly C, Ziff EB (1997) Post-transcriptional regulation of synaptic vesicle protein expression and the developmental control of synaptic vesicle formation. J Neurosci 17(7):2365–2375PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2006

Authors and Affiliations

  • Cristina A. Ghiani
    • 1
  • Luis Beltran-Parrazal
    • 2
  • Daniel M. Sforza
    • 3
    • 5
  • Jemily S. Malvar
    • 1
  • Akop Seksenyan
    • 1
  • Ruth Cole
    • 1
  • Desmond J. Smith
    • 3
  • Andrew Charles
    • 2
  • Pedro A. Ferchmin
    • 4
  • Jean de Vellis
    • 1
  1. 1.Mental Retardation Research Center, Jane and Terry Semel Institute for Neuroscience and Human Behaviour, Departments of Neurobiology and Psychiatry, David Geffen School of MedicineUniversity of California at Los AngelesLos AngelesUSA
  2. 2.Department of Neurology, David Geffen School of MedicineUniversity of California at Los AngelesLos AngelesUSA
  3. 3.Department of Molecular and Medical Pharmacology, David Geffen School of MedicineUniversity of California at Los AngelesLos AngelesUSA
  4. 4.Department of BiochemistryUniversidad Central del CaribeBayamónUSA
  5. 5.Laboratory of NeuroImaging, Department of Neurology, David Geffen School of MedicineUniversity of California at Los AngelesLos AngelesUSA

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