Molecular Neurobiology

, Volume 49, Issue 3, pp 1472–1486 | Cite as

Epigenetic Modulation of Adult Hippocampal Neurogenesis by Extremely Low-Frequency Electromagnetic Fields

  • Lucia Leone
  • Salvatore Fusco
  • Alessia Mastrodonato
  • Roberto Piacentini
  • Saviana Antonella Barbati
  • Salvatore Zaffina
  • Giovambattista Pani
  • Maria Vittoria Podda
  • Claudio Grassi
Article

Abstract

Throughout life, adult neurogenesis generates new neurons in the dentate gyrus of hippocampus that have a critical role in memory formation. Strategies able to stimulate this endogenous process have raised considerable interest because of their potential use to treat neurological disorders entailing cognitive impairment. We previously reported that mice exposed to extremely low-frequency electromagnetic fields (ELFEFs) showed increased hippocampal neurogenesis. Here, we demonstrate that the ELFEF-dependent enhancement of hippocampal neurogenesis improves spatial learning and memory. To gain insights on the molecular mechanisms underlying ELFEFs’ effects, we extended our studies to an in vitro model of neural stem cells (NSCs) isolated from the hippocampi of newborn mice. We found that ELFEFs enhanced proliferation and neuronal differentiation of hippocampal NSCs by regulation of epigenetic mechanisms leading to pro-neuronal gene expression. Upon ELFEF stimulation of NSCs, we observed a significant enhancement of expression of the pro-proliferative gene hairy enhancer of split 1 and the neuronal determination genes NeuroD1 and Neurogenin1. These events were preceded by increased acetylation of H3K9 and binding of the phosphorylated transcription factor cAMP response element-binding protein (CREB) on the regulatory sequence of these genes. Such ELFEF-dependent epigenetic modifications were prevented by the Cav1-channel blocker nifedipine, and were associated with increased occupancy of CREB-binding protein (CBP) to the same loci within the analyzed promoters. Our results unravel the molecular mechanisms underlying the ELFEFs’ ability to improve endogenous neurogenesis, pointing to histone acetylation–related chromatin remodeling as a critical determinant. These findings could pave the way to the development of novel therapeutic approaches in regenerative medicine.

Keywords

Hippocampal neural stem cells CREB Cav1 channels Epigenetics Hes1 NeuroD1 and Neurogenin1 modulation Spatial memory 

Supplementary material

12035_2014_8650_Fig8_ESM.jpg (106 kb)
Supplemental Fig. 1

Adult hippocampal neurogenesis is increased by ELFEF exposure. Confocal images of BrdU and DCX labeling in representative sagittal sections of the DG from control (a) and ELFEF-exposed mice (12D × 3.5 h; b). Double-labeled cells (BrdU+/DCX+) are more numerous in sections from exposed mice. Scale bar, 75 μm. c Bar graph showing absolute number of newly generated immature neurons (BrdU+/DCX+ cells) in the GCL + SGZ of mice exposed to ELFEFs. **p < 0.001 (JPEG 105 kb)

12035_2014_8650_MOESM1_ESM.tif (4.2 mb)
High-resolution image (TIFF 4263 kb)
12035_2014_8650_Fig9_ESM.jpg (116 kb)
Supplemental Fig. 2

Hippocampal neurogenesis enhancement detected one month after ELFEF exposure. Confocal images of BrdU and NeuN labeling in representative sagittal sections of the DG from control (a) and ELFEF-exposed mice (b). The number of double-labeled BrdU+/NeuN+ cells is higher in sections from exposed mice. Arrowheads show migration of new dentate granule cells into the GCL. Scale bar, 75 μm. c Bar graph showing total number of mature neurons (BrdU+/NeuN+ cells) in the GCL of control and exposed mice. **p < 0.005 (JPEG 115 kb)

12035_2014_8650_MOESM2_ESM.tif (5.8 mb)
High-resolution image (TIFF 5910 kb)
12035_2014_8650_Fig10_ESM.jpg (36 kb)
Supplemental Fig. 3

Effects of ELFEFs on the global H3K9 acetylation in proliferating and differentiating NSCs. Representative Western immunoblot showing no significant differences of global H3K9 acetylation (H3K9Ac) on ELFEF-exposed NSCs in both proliferative (P) and differentiative (D) culture conditions. Tubulin bands confirm equal protein loading. Picture is representative of two independent experiments (JPEG 35 kb)

12035_2014_8650_MOESM3_ESM.tif (77 kb)
High-resolution image (TIFF 76 kb)

References

  1. 1.
    Kempermann G, Wiskott L, Gage FH (2004) Functional significance of adult neurogenesis. Curr Opin Neurobiol 14:186–191PubMedCrossRefGoogle Scholar
  2. 2.
    Ming GL, Song H (2011) Adult neurogenesis in the mammalian brain: significant answers and significant questions. Neuron 70:687–702PubMedCentralPubMedCrossRefGoogle Scholar
  3. 3.
    Zhao C, Teng EM, Summers RG Jr et al (2006) Distinct morphological stages of dentate granule neuron maturation in the adult mouse hippocampus. J Neurosci 26:3–11PubMedCrossRefGoogle Scholar
  4. 4.
    Aimone JB, Deng W, Gage FH (2011) Resolving new memories: a critical look at the dentate gyrus, adult neurogenesis, and pattern separation. Neuron 70:589–596PubMedCentralPubMedCrossRefGoogle Scholar
  5. 5.
    Kee N, Teixeira CM, Wang AH et al (2007) Imaging activation of adult-generated granule cells in spatial memory. Nat Protoc 2:3033–3044PubMedCrossRefGoogle Scholar
  6. 6.
    Marín-Burgin A, Schinder AF (2012) Requirement of adult-born neurons for hippocampus-dependent learning. Behav Brain Res 227:391–399PubMedCrossRefGoogle Scholar
  7. 7.
    Shors TJ, Miesegaes G, Beylin AV et al (2001) Neurogenesis in the adult is involved in the formation of trace memories. Nature 410:372–376PubMedCrossRefGoogle Scholar
  8. 8.
    Vivar C, van Praag H (2013) Functional circuits of new neurons in the dentate gyrus. Front Neural Circuits 7:15PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    Bellenchi GC, Volpicelli F, Piscopo V et al (2013) Adult neural stem cells: an endogenous tool to repair brain injury? J Neurochem 124:159–167PubMedCrossRefGoogle Scholar
  10. 10.
    Encinas JM, Sierra A (2012) Neural stem cell deforestation as the main force driving the age-related decline in adult hippocampal neurogenesis. Behav Brain Res 227:433–439PubMedCrossRefGoogle Scholar
  11. 11.
    Taylor CJ, Jhaveri DJ, Bartlett PF (2013) The therapeutic potential of endogenous hippocampal stem cells for the treatment of neurological disorders. Front Cell Neurosci 7:5PubMedCentralPubMedGoogle Scholar
  12. 12.
    Brown J, Cooper-Kuhn CM, Kempermann G et al (2003) Enriched environment and physical activity stimulate hippocampal but not olfactory bulb neurogenesis. Eur J Neurosci 17:2042–2046PubMedCrossRefGoogle Scholar
  13. 13.
    Kempermann G (2012) New neurons for ‘survival of the fittest’. Nat Rev Neurosci 13:727–736PubMedGoogle Scholar
  14. 14.
    van Praag H, Christie BR, Sejnowski TJ et al (1999) Running enhances neurogenesis, learning, and long-term potentiation in mice. Proc Natl Acad Sci U S A 96:13427–13431PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    Arias-Carrión O, Verdugo-Díaz L, Feria-Velasco A et al (2004) Neurogenesis in the subventricular zone following transcranial magnetic field stimulation and nigrostriatal lesions. J Neurosci Res 78:16–28PubMedCrossRefGoogle Scholar
  16. 16.
    Cuccurazzu B, Leone L, Podda MV et al (2010) Exposure to extremely low-frequency (50 Hz) electromagnetic fields enhances adult hippocampal neurogenesis in C57BL/6 mice. Exp Neurol 226:173–182PubMedCrossRefGoogle Scholar
  17. 17.
    Podda MV, Leone L, Barbati SA et al. (2014) Extremely low-frequency electromagnetic fields enhance the survival of newborn neurons in the mouse hippocampus. Eur J NeurosciGoogle Scholar
  18. 18.
    Czéh B, Welt T, Fischer AK et al (2002) Chronic psychosocial stress and concomitant repetitive transcranial magnetic stimulation: effects on stress hormone levels and adult hippocampal neurogenesis. Biol Psychiatry 52:1057–1065PubMedCrossRefGoogle Scholar
  19. 19.
    Hansson Mild K, Alanko T, Decat G et al (2009) Exposure of workers to electromagnetic fields. A review of open questions on exposure assessment techniques. Int J Occup Saf Ergon 15:3–33PubMedGoogle Scholar
  20. 20.
    Piacentini R, Ripoli C, Mezzogori D et al (2008) Extremely low-frequency electromagnetic fields promote in vitro neurogenesis via upregulation of Ca(v)1-channel activity. J Cell Physiol 215:129–139PubMedCrossRefGoogle Scholar
  21. 21.
    Hsieh J (2012) Orchestrating transcriptional control of adult neurogenesis. Genes Dev 26:1010–1021PubMedCentralPubMedCrossRefGoogle Scholar
  22. 22.
    Nieber F, Pieler T, Henningfeld KA (2009) Comparative expression analysis of the neurogenins in Xenopus tropicalis and Xenopus laevis. Dev Dyn 238:451–458PubMedCrossRefGoogle Scholar
  23. 23.
    Sommer L, Ma Q, Anderson DJ (1996) Neurogenins, a novel family of atonal-related bHLH transcription factors, are putative mammalian neuronal determination genes that reveal progenitor cell heterogeneity in the developing CNS and PNS. Mol Cell Neurosci 8:221–241PubMedCrossRefGoogle Scholar
  24. 24.
    Bai G, Sheng N, Xie Z et al (2007) Id sustains Hes1 expression to inhibit precocious neurogenesis by releasing negative autoregulation of Hes1. Dev Cell 13:283–297PubMedCrossRefGoogle Scholar
  25. 25.
    Boutin C, Hardt O, de Chevigny A et al (2010) NeuroD1 induces terminal neuronal differentiation in olfactory neurogenesis. Proc Natl Acad Sci U S A 107:1201–1216PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    Kim EJ, Ables JL, Dickel LK et al (2011) Ascl1 (Mash1) defines cells with long-term neurogenic potential in subgranular and subventricular zones in adult mouse brain. PLoS ONE 6:e18472PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Lo L, Tiveron MC, Anderson DJ (1998) MASH1 activates expression of the paired homeodomain transcription factor Phox2a, and couples pan-neuronal and subtype-specific components of autonomic neuronal identity. Development 125:609–620PubMedGoogle Scholar
  28. 28.
    Sun Y, Nadal-Vicens M, Misono S et al (2001) Neurogenin promotes neurogenesis and inhibits glial differentiation by independent mechanisms. Cell 104:365–376PubMedCrossRefGoogle Scholar
  29. 29.
    Jenuwein T, Allis CD (2001) Translating the histone code. Science 293:1074–1080PubMedCrossRefGoogle Scholar
  30. 30.
    Crepaldi L, Riccio A (2009) Chromatin learns to behave. Epigenetics 4:23–26PubMedCrossRefGoogle Scholar
  31. 31.
    Gräff J, Tsai LH (2013) Histone acetylation: molecular mnemonics on the chromatin. Nat Rev Neurosci 14:97–111PubMedCrossRefGoogle Scholar
  32. 32.
    Lee S, Lee SK (2010) Crucial roles of histone-modifying enzymes in mediating neural cell-type specification. Curr Opin Neurobiol 20:29–36PubMedCentralPubMedCrossRefGoogle Scholar
  33. 33.
    Olynik BM, Rastegar M (2012) The genetic and epigenetic journey of embryonic stem cells into mature neural cells. Front Genet 3:81PubMedCentralPubMedCrossRefGoogle Scholar
  34. 34.
    Cho B, Kim HJ, Kim H et al (2011) Changes in the histone acetylation patterns during the development of the nervous system. Exp Neurobiol 20:81–84PubMedCentralPubMedCrossRefGoogle Scholar
  35. 35.
    Lilja T, Heldring N, Hermanson O (2013) Like a rolling histone: epigenetic regulation of neural stem cells and brain development by factors controlling histone acetylation and methylation. Biochim Biophys Acta 1830:2354–2360PubMedCrossRefGoogle Scholar
  36. 36.
    Day JJ, Sweatt JD (2011) Epigenetic mechanisms in cognition. Neuron 70:813–829PubMedCentralPubMedCrossRefGoogle Scholar
  37. 37.
    Miller CA, Campbell SL, Sweatt JD (2008) DNA methylation and histone acetylation work in concert to regulate memory formation and synaptic plasticity. Neurobiol Learn Mem 89:599–603PubMedCentralPubMedCrossRefGoogle Scholar
  38. 38.
    Roth TL, Sweatt JD (2009) Regulation of chromatin structure in memory formation. Curr Opin Neurobiol 19:336–342PubMedCentralPubMedCrossRefGoogle Scholar
  39. 39.
    Sharma SK (2010) Protein acetylation in synaptic plasticity and memory. Neurosci Biobehav Rev 34:1234–1240PubMedCrossRefGoogle Scholar
  40. 40.
    Sui L, Wang Y, Ju LH et al (2012) Epigenetic regulation of reelin and brain-derived neurotrophic factor genes in long-term potentiation in rat medial prefrontal cortex. Neurobiol Learn Mem 97:425–440PubMedCrossRefGoogle Scholar
  41. 41.
    Gräff J, Mansuy IM (2009) Epigenetic dysregulation in cognitive disorders. Eur J Neurosci 30:1–8PubMedCrossRefGoogle Scholar
  42. 42.
    Tsankova N, Renthal W, Kumar A et al (2007) Epigenetic regulation in psychiatric disorders. Nat Rev Neurosci 8:355–367PubMedCrossRefGoogle Scholar
  43. 43.
    Grassi C, D’Ascenzo M, Torsello A et al (2004) Effects of 50 Hz electromagnetic fields on voltage-gated Ca2+ channels and their role in modulation of neuroendocrine cell proliferation and death. Cell Calcium 35:307–315PubMedCrossRefGoogle Scholar
  44. 44.
    Wolf FI, Torsello A, Tedesco B et al (2005) 50-Hz extremely low frequency electromagnetic fields enhance cell proliferation and DNA damage: possible involvement of a redox mechanism. Biochim Biophys Acta 1743:120–129PubMedCrossRefGoogle Scholar
  45. 45.
    Kempermann G, Gage FH (2002) Genetic determinants of adult hippocampal neurogenesis correlate with acquisition, but not probe trial performance, in the water maze task. Eur J Neurosci 16:129–136PubMedCrossRefGoogle Scholar
  46. 46.
    Leone L, De Stefano ME, Del Signore A et al (2005) Axotomy of sympathetic neurons activates the metalloproteinase-2 enzymatic pathway. J Neuropathol Exp Neurol 64:1007–1017PubMedCrossRefGoogle Scholar
  47. 47.
    Podda MV, D’Ascenzo M, Leone L et al (2008) Functional role of cyclic nucleotide-gated channels in rat medial vestibular nucleus neurons. J Physiol 586:803–815PubMedCentralPubMedCrossRefGoogle Scholar
  48. 48.
    Podda MV, Leone L, Piacentini R et al (2012) Expression of olfactory-type cyclic nucleotide-gated channels in rat cortical astrocytes. Glia 60:1391–1405PubMedCrossRefGoogle Scholar
  49. 49.
    Mayhew TM, Gundersen HJ (1996) If you assume, you can make an ass out of u and me’: a decade of the disector for stereological counting of particles in 3D space. J Anat 188:1–15PubMedCentralPubMedGoogle Scholar
  50. 50.
    West MJ (1999) Stereological methods for estimating the total number of neurons and synapses: issues of precision and bias. Trends Neurosci 22:51–61PubMedCrossRefGoogle Scholar
  51. 51.
    Podda MV, Piacentini R, Barbati SA et al (2013) Role of cyclic nucleotide-gated channels in the modulation of mouse hippocampal neurogenesis. PLoS ONE. doi:10.1371/journal.pone.0073246 Google Scholar
  52. 52.
    D’Ascenzo M, Piacentini R, Casalbore P et al (2006) Role of L-type Ca2+ channels in neural stem/progenitor cell differentiation. Eur J Neurosci 23:935–944PubMedCrossRefGoogle Scholar
  53. 53.
    Curcio L, Podda MV, Leone L et al (2013) Reduced d-serine levels in the nucleus accumbens of cocaine-treated rats hinder the induction of NMDA receptor-dependent synaptic plasticity. Brain 136:1216–1230PubMedCrossRefGoogle Scholar
  54. 54.
    Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)). Methods 25:402–408PubMedCrossRefGoogle Scholar
  55. 55.
    Fusco S, Ripoli C, Podda MV et al (2012) A role for neuronal CREB (cAMP responsive element binding)-1 in brain responses to calorie restriction. Proc Natl Acad Sci U S A 109:621–626PubMedCentralPubMedCrossRefGoogle Scholar
  56. 56.
    Gaudillière B, Konishi Y, de la Iglesia N et al (2004) A CaMKII-NeuroD signaling pathway specifies dendritic morphogenesis. Neuron 41:229–241PubMedCrossRefGoogle Scholar
  57. 57.
    Ince-Dunn G, Hall BJ, Hu SC et al (2006) Regulation of thalamocortical patterning and synaptic maturation by NeuroD2. Neuron 49:683–695PubMedCrossRefGoogle Scholar
  58. 58.
    Olson JM, Asakura A, Snider L et al (2001) NeuroD2 is necessary for development and survival of central nervous system neurons. Dev Biol 234:174–187PubMedCrossRefGoogle Scholar
  59. 59.
    Pleasure SJ, Collins AE, Lowenstein DH (2000) Unique expression patterns of cell fate molecules delineate sequential stages of dentate gyrus development. J Neurosci 20:6095–6105PubMedGoogle Scholar
  60. 60.
    Di Lazzaro V, Capone F, Apollonio F et al (2013) A consensus panel review of central nervous system effects of the exposure to low-intensity extremely low-frequency magnetic fields. Brain Stimul 6:469–476PubMedCrossRefGoogle Scholar
  61. 61.
    Machado S, Paes F, Velasques B et al (2012) Is rTMS an effective therapeutic strategy that can be used to treat anxiety disorders? Neuropharmacology 62:125–134PubMedCrossRefGoogle Scholar
  62. 62.
    Hatakeyama J, Kageyama R (2004) Retinal cell fate determination and bHLH factors. Semin Cell Dev Biol 15:83–89PubMedCrossRefGoogle Scholar
  63. 63.
    Ishibashi M, Ang SL, Shiota K et al (1995) Targeted disruption of mammalian hairy and enhancer of split homolog-1 (HES-1) leads to up-regulation of neural helix–loop–helix factors, premature neurogenesis, and severe neural tube defects. Genes Dev 9:3136–3148PubMedCrossRefGoogle Scholar
  64. 64.
    Tomita K, Nakanishi S, Guillemot F et al (1996) Mash1 promotes neuronal differentiation in the retina. Genes Cells 1:765–774PubMedCrossRefGoogle Scholar
  65. 65.
    Shimojo H, Ohtsuka T, Kageyama R (2011) Dynamic expression of Notch signaling genes in neural stem/progenitor cells. Front Neurosci 5:1–7CrossRefGoogle Scholar
  66. 66.
    Zhou X, Smith AJ, Waterhouse A et al (2013) Hes1 desynchronizes differentiation of pluripotent cells by modulating STAT3 activity. Stem Cells 31:1511–1522PubMedCrossRefGoogle Scholar
  67. 67.
    Fu J, Tay SS, Ling EA, Dheen ST (2006) High glucose alters the expression of genes involved in proliferation and cell-fate specification of embryonic neural stem cells. Diabetologia 49:1027–1038PubMedCrossRefGoogle Scholar
  68. 68.
    Zhuang PW, Cui GZ, Zhang YJ et al (2013) Baicalin regulates neuronal fate decision in neural stem/progenitor cells and stimulates hippocampal neurogenesis in adult rats. CNS Neurosci Ther 19:154–162PubMedCrossRefGoogle Scholar
  69. 69.
    Sinnegger-Brauns MJ, Huber IG, Koschak A et al (2009) Expression and 1,4-dihydropyridine-binding properties of brain l-type calcium channel isoforms. Mol Pharmacol 75:407–414PubMedCrossRefGoogle Scholar
  70. 70.
    Morgado-Valle C, Verdugo-Díaz L, García DE et al (1998) The role of voltage-gated Ca2+ channels in neurite growth of cultured chromaffin cells induced by extremely low frequency (ELF) magnetic field stimulation. Cell Tissue Res 291:217–230PubMedCrossRefGoogle Scholar
  71. 71.
    Olivares-Bañuelos T, Navarro L, González A et al (2004) Differentiation of chromaffin cells elicited by ELF MF modifies gene expression pattern. Cell Biol Int 28:273–279PubMedCrossRefGoogle Scholar
  72. 72.
    Deisseroth K, Singla S, Toda H et al (2004) Excitation–neurogenesis coupling in adult neural stem/progenitor cells. Neuron 42:535–552PubMedCrossRefGoogle Scholar
  73. 73.
    Ramírez M, Hernández-Montoya J, Sánchez-Serrano SL et al (2012) GABA-mediated induction of early neuronal markers expression in postnatal rat progenitor cells in culture. Neuroscience 224:210–222PubMedCrossRefGoogle Scholar
  74. 74.
    West AE, Chen WG, Dalva MB et al (2001) Calcium regulation of neuronal gene expression. Proc Natl Acad Sci U S A 98:11024–11031PubMedCentralPubMedCrossRefGoogle Scholar
  75. 75.
    Jagasia R, Steib K, Englberger E et al (2009) GABA-cAMP response element-binding protein signaling regulates maturation and survival of newly generated neurons in the adult hippocampus. J Neurosci 29:7966–7977PubMedCentralPubMedCrossRefGoogle Scholar
  76. 76.
    Merz K, Herold S, Lie DC (2011) CREB in adult neurogenesis–master and partner in the development of adult-born neurons. Eur J Neurosci 33:1078–1086PubMedCrossRefGoogle Scholar
  77. 77.
    Benito E, Barco A (2010) CREB’s control of intrinsic and synaptic plasticity: implications for CREB-dependent memory models. Trends Neurosci 33:230–240PubMedCrossRefGoogle Scholar
  78. 78.
    Bito H, Takemoto-Kimura S (2003) Ca(2+)/CREB/CBP-dependent gene regulation: a shared mechanism critical in long-term synaptic plasticity and neuronal survival. Cell Calcium 34:425–430PubMedCrossRefGoogle Scholar
  79. 79.
    Wang J, Weaver IC, Gauthier-Fisher A et al (2010) CBP histone acetyltransferase activity regulates embryonic neural differentiation in the normal and Rubinstein–Taybi syndrome brain. Dev Cell 18:114–125PubMedCrossRefGoogle Scholar
  80. 80.
    Min SW, Cho SH, Zhou Y et al (2010) Acetylation of tau inhibits its degradation and contributes to tauopathy. Neuron 67:953–966PubMedCentralPubMedCrossRefGoogle Scholar
  81. 81.
    Prozorovski T, Schulze-Topphoff U, Glumm R et al (2008) Sirt1 contributes critically to the redox-dependent fate of neural progenitors. Nat Cell Biol 10:385–394PubMedCrossRefGoogle Scholar
  82. 82.
    Gaub P, Tedeschi A, Puttagunta R et al (2010) HDAC inhibition promotes neuronal outgrowth and counteracts growth cone collapse through CBP/p300 and P/CAF-dependent p53 acetylation. Cell Death Differ 17:1392–1408PubMedCrossRefGoogle Scholar
  83. 83.
    Foti SB, Chou A, Moll AD et al (2013) HDAC inhibitors dysregulate neural stem cell activity in the postnatal mouse brain. Int J Dev Neurosci 31:434–447PubMedCrossRefGoogle Scholar
  84. 84.
    Chatterjee S, Mizar P, Cassel R et al (2013) A novel activator of CBP/p300 acetyltransferases promotes neurogenesis and extends memory duration in adult mice. J Neurosci 33:10698–10712PubMedCrossRefGoogle Scholar
  85. 85.
    Huang HY, Liu DD, Chang HF et al (2012) Histone deacetylase inhibition mediates urocortin-induced antiproliferation and neuronal differentiation in neural stem cells. Stem Cells 30:2760–2773PubMedCrossRefGoogle Scholar
  86. 86.
    Yu IT, Park JY, Kim SH et al (2009) Valproic acid promotes neuronal differentiation by induction of proneural factors in association with H4 acetylation. Neuropharmacology 56:473–480PubMedCrossRefGoogle Scholar
  87. 87.
    Shibasaki M, Mizuno K, Kurokawa K et al (2011) l-type voltage-dependent calcium channels facilitate acetylation of histone H3 through PKCγ phosphorylation in mice with methamphetamine-induced place preference. J Neurochem 118:1056–1066PubMedCrossRefGoogle Scholar
  88. 88.
    Chen X, Lepier A, Berninger B et al (2012) Cultured subventricular zone progenitor cells transduced with neurogenin-2 become mature glutamatergic neurons and integrate into the dentate gyrus. PLoS ONE 7:e31547PubMedCentralPubMedCrossRefGoogle Scholar
  89. 89.
    Cho IS, Jung M, Kwon KS et al (2012) Deregulation of CREB signaling pathway induced by chronic hyperglycemia downregulates NeuroD transcription. PLoS ONE 7:e34860. doi:10.1371/journal.pone.0034860 PubMedCentralPubMedCrossRefGoogle Scholar
  90. 90.
    Liu M, Pleasure SJ, Collins AE et al (2000) Loss of BETA2/NeuroD leads to malformation of the dentate gyrus and epilepsy. Proc Natl Acad Sci U S A 97:865–870PubMedCentralPubMedCrossRefGoogle Scholar
  91. 91.
    Fedele V, Roybon L, Nordström U et al (2011) Neurogenesis in the R6/2 mouse model of Huntington’s disease is impaired at the level of NeuroD1. Neuroscience 173:76–81PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Lucia Leone
    • 1
  • Salvatore Fusco
    • 1
  • Alessia Mastrodonato
    • 1
  • Roberto Piacentini
    • 1
  • Saviana Antonella Barbati
    • 1
  • Salvatore Zaffina
    • 2
  • Giovambattista Pani
    • 3
  • Maria Vittoria Podda
    • 1
  • Claudio Grassi
    • 1
  1. 1.Institute of Human Physiology, Medical SchoolUniversità CattolicaRomeItaly
  2. 2.Children’s Hospital “Bambino Gesù”RomeItaly
  3. 3.Institute of General Pathology, Medical SchoolUniversità CattolicaRomeItaly

Personalised recommendations