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

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.

Impact of electromagnetic fields on stem cells: common mechanisms at the crossroad between adult neurogenesis and osteogenesis

“…This study shed further light on molecular mechanisms underlying ELFEFs’ effects revealing a significant regulation of epigenetic mechanisms leading to pro-neuronal gene expression. In particular, in in vitro and in vivo models of adult hippocampal neurogenesis we demonstrated that enhanced expression of Hes1 in proliferating NSCs and NeuroD1 , and Neurogenin1 in differentiating NSCs were associated to increased H3K9 acetylation and Ca 2+ -dependent CREB/CBP recruitment on the regulatory sequence of these genes (Leone et al, 2014). This study suggested that regulation of epigenetic mechanism provides a fine and targeted control of neurogenic process by ELFEFs.…”

“…A similar molecular mechanism has been described for the transcription factor cAMP response element-binding protein (CREB), which modulates neuronal differentiation by binding regulatory sequences of pro-neural genes (Deisseroth et al, 2004; Jagasia et al, 2009). In particular, Ca 2+ signaling triggers phosphorylation of CREB, that, once activated, promotes NSC differentiation (West et al, 2001; Giachino et al, 2005; D’Ascenzo et al, 2006; Leone et al, 2014). …”

“…Importantly, our most recent study demonstrated that the ELFEF-induced enhancement of hippocampal neurogenesis and synaptic plasticity lead to improved hippocampal-dependent learning and memory in mice (Leone et al, 2014). This study shed further light on molecular mechanisms underlying ELFEFs’ effects revealing a significant regulation of epigenetic mechanisms leading to pro-neuronal gene expression.…”

“…As such SCs hold promise for tissue/organ repair with the ultimate goal to regenerate and restore normal functions. Adult SCs are most often in a quiescent state, and either or both intrinsic or extrinsic factors can trigger programs for self-renewal or differentiation (Kobilo et al, 2011; Podda et al, 2013; Leone et al, 2014). It is currently accepted that a combination of niche signals and cell intrinsic programs orchestrate the transition from an undifferentiated stem cell state to a progenitor cell committed to the final fate.…”

A role for histone acetylation mechanisms in adolescent alcohol exposure-induced deficits in hippocampal brain-derived neurotrophic factor expression and neurogenesis markers in adulthood

“…Histone acetylation also regulates adult neurogenesis in preclinical models (Leone et al 2014; Swaminathan et al 2014; Yoo et al 2015). Recently, we observed the ability of HDAC inhibitors, such as trichostatin A (TSA), to reverse adolescent intermittent ethanol (AIE) exposure-induced anxiety-like and alcohol drinking behaviors, as well as reverse the deficits in histone H3-K9&14 acetylation of the BDNF gene in the amygdala during adulthood (Pandey et al 2015).…”