Epigenetic modulation of adult hippocampal neurogenesis by extremely low-frequency electromagnetic fields

Throughout life, adult neurogenesis generates newneurons in the dentate gyrus of hippocampus that have acritical role in memory formation. Strategies able to stimulatethis endogenous process have raised considerable interestbecause of their potential use to treat neurological disordersentailing cognitive impairment. We previously reported thatmice exposed to extremely low-frequency electromagneticfields (ELFEFs) showed increased hippocampalneurogenesis. Here, we demonstrate that the ELFEFdependentenhancement of hippocampal neurogenesis improvesspatial learning and memory. To gain insights on themolecular mechanisms underlying ELFEFs’ effects, we extendedour studies to an in vitro model of neural stem cells(NSCs) isolated from the hippocampi of newborn mice. Wefound that ELFEFs enhanced proliferation and neuronal differentiationof hippocampal NSCs by regulation of epigeneticmechanisms leading to pro-neuronal gene expression. UponELFEF stimulation of NSCs, we observed a significant enhancementof expression of the pro-proliferative gene hairyenhancer of split 1 and the neuronal determination genesNeuroD1 and Neurogenin1. These events were preceded byincreased acetylation of H3K9 and binding of the phosphorylatedtranscription factor cAMP response element-bindingprotein (CREB) on the regulatory sequence of these genes.Such ELFEF-dependent epigenetic modifications wereprevented by the Cav1-channel blocker nifedipine, and wereassociated with increased occupancy of CREB-binding protein(CBP) to the same loci within the analyzed promoters.Our results unravel the molecular mechanisms underlying theELFEFs’ ability to improve endogenous neurogenesis,pointing to histone acetylation–related chromatin remodelingas a critical determinant. These findings could pave the way tothe development of novel therapeutic approaches in regenerativemedicine.