Shaping synaptic plasticity: the role of activity-mediated epigenetic regulation on gene transcription

Int J Dev Neurosci. 2013 Oct;31(6):359-69. doi: 10.1016/j.ijdevneu.2013.04.003. Epub 2013 May 9.


Learning and memory are basic functions of the brain that allowed human evolution. It is well accepted that during learning and memory formation the dynamic establishment of new active synaptic connections is crucial. Persistent synaptic activation leads to molecular events that include increased release of neurotransmitters, increased expression of receptors on the postsynaptic neuron, thus creating a positive feedback that results in the activation of distinct signaling pathways that temporally and permanently alter specific patterns of gene expression. However, the epigenetic changes that allow the establishment of long term genetic programs that control learning and memory are not completely understood. Even less is known regarding the signaling events triggered by synaptic activity that regulate these epigenetic marks. Here we review the current understanding of the molecular mechanisms controlling activity-dependent gene transcription leading synaptic plasticity and memory formation. We describe how Ca(2+) entry through N-methyl-d-aspartate-type glutamate neurotransmitter receptors result in the activation of specific signaling pathways leading to changes in gene expression, giving special emphasis to the recent data pointing out different epigenetic mechanisms (histone acetylation, methylation and phosphorylation as well as DNA methylation and hydroxymethylation) underlying learning and memory.

Keywords: (5hmC); (BDNF); (CAMK); (CBP); (CRE); (CREB); (CREM); (CaM); (CaN); (CaRE); (CaRF); (CpG); (DNMTs); (H); (HATs); (HDACs); (IEGs); (LTD); (LTP); (MBD); (MSK); (MeCP2); (Mll); (NFAT); (NGF); (NMDA); (NMDARs); (PP1); (RSK); (TET); (TORCs); (TSA); (USF1/2); ([Ca(2+)]); (cAMP); BDNF; CREB; CREB binding protein; Ca(2+) response element; Ca(2+) signaling; Ca(2+)-responsive transcription factor; Ca(2+)/CaM-dependent kinase; Chromatin remodeling; Cytosine hydroxymethylation; DNA methylation; DNA methyltransferases; Epigenetics; MeCP2; N-methyl-d-aspartate; NMDA receptors; Signal transduction; Synaptic plasticity; TET; Transcription factors; Trichostatin A; VGCCs; brain-derived neurotrophic factor; cAMP response element; cAMP response element binding protein; cAMP response element modulator; calcineurin; calcium concentration; calmodulin; cyclic adenosine monophosphate; cytosine hydroxymethylation; histone; histone acetyl transferases; histone deacetylases; immediate-early genes; long-term depression; long-term potentiation; methyl-CpG binding protein 2; methyl-CpG binding protein family; mitogen- and stress-activated protein kinase; mixed-lineage leukemia; nerve growth factor; nuclear factor of activated T-cells; palindromic 5′-CG-3′ dinucleotide; protein phosphatase 1; ribosomal S6 kinase; stimulatory factors 1 and 2; ten-eleven translocation protein family; transducers of regulated CREB activity; voltage-gated calcium channels.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Epigenesis, Genetic / physiology*
  • Humans
  • Neuronal Plasticity / physiology*
  • Receptors, N-Methyl-D-Aspartate / genetics
  • Receptors, N-Methyl-D-Aspartate / physiology
  • Signal Transduction / physiology
  • Synapses / physiology*
  • Transcription, Genetic*


  • Receptors, N-Methyl-D-Aspartate