Molecular Neurobiology

, Volume 49, Issue 3, pp 1472–1486

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

DOI: 10.1007/s12035-014-8650-8

Cite this article as:
Leone, L., Fusco, S., Mastrodonato, A. et al. Mol Neurobiol (2014) 49: 1472. doi:10.1007/s12035-014-8650-8

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 cellsCREBCav1 channelsEpigeneticsHes1NeuroD1 and Neurogenin1 modulationSpatial 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. 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_MOESM2_ESM.tif (5.8 mb)
High-resolution image (TIFF 5910 kb)
12035_2014_8650_Fig10_ESM.jpg (36 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_MOESM3_ESM.tif (77 kb)
High-resolution image (TIFF 76 kb)

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