The complexity of long-term memory (LTM) formation is astounding. A simplified version could be described as requiring ordered communication between different brain regions to process multiple modes of external input, activation at discrete synapses on specific cell types, and a tightly regulated program of gene transcription and protein translation, followed by trafficking of certain plasticity-related proteins back to the synaptic site of activation. In light of these many, ordered steps, the relatively rare occurrence of memory failure is a testament to how carefully the brain regulates cognition. Fascination with what might orchestrate the highly complex transcriptional program that supports memory, as well as the hope of identifying new therapeutic targets, has led a number of investigators to epigenetics.

The term epigenetics, first coined by Conrad Waddington in the 1940s, refers to changes that occur above (‘epi-’) the genome. Epigenetics has traditionally been studied in terms of development, differentiation, and disease states that involve unchecked transcription, such as cancer. The observed stability of epigenetic marks led to the traditional definition of epigenetics as the study of heritable changes in phenotype or gene expression that do not involve changes to the DNA sequence itself. However, recent epigenetic investigations in the adult brain have revealed that these mechanisms can modify neuronal gene transcription in very important ways that do not necessarily alter heritability.

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