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

• Changes in gene transcription are required for the establishment of LTP.
• Bdnf and c-fos are highly regulated in response to neuronal activity.
• Changes in histone postranslational modifications occur during learning paradigms.
• Neural activity induces active DNA methylation and demethylation.
• TET proteins and cytosine hydroxymethylation are new mechanisms regulating memory.

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 Ca2+ 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.

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