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

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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.

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Acknowledgments

This work was supported by grants from the Italian Ministry of Health (RF-2009-1543811) and from the Catholic University (D3.2 and D1 funds).

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Authors and Affiliations

  1. Institute of Human Physiology, Medical School, Università Cattolica, Largo Francesco Vito 1, 00168, Rome, Italy

    Lucia Leone, Salvatore Fusco, Alessia Mastrodonato, Roberto Piacentini, Saviana Antonella Barbati, Maria Vittoria Podda & Claudio Grassi

  2. Children’s Hospital “Bambino Gesù”, Rome, Italy

    Salvatore Zaffina

  3. Institute of General Pathology, Medical School, Università Cattolica, Rome, Italy

    Giovambattista Pani

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  1. Lucia Leone
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  2. Salvatore Fusco
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  3. Alessia Mastrodonato
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  4. Roberto Piacentini
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  5. Saviana Antonella Barbati
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  6. Salvatore Zaffina
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  7. Giovambattista Pani
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  8. Maria Vittoria Podda
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Correspondence to Claudio Grassi.

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Lucia Leone and Salvatore Fusco equally contributed to this work.

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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)

High-resolution image (TIFF 4263 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)

High-resolution image (TIFF 5910 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)

High-resolution image (TIFF 76 kb)

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Leone, L., Fusco, S., Mastrodonato, A. et al. Epigenetic Modulation of Adult Hippocampal Neurogenesis by Extremely Low-Frequency Electromagnetic Fields. Mol Neurobiol 49, 1472–1486 (2014). https://doi.org/10.1007/s12035-014-8650-8

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