DNA methylation and memory formation

Journal name:
Nature Neuroscience
Year published:
Published online


Memory formation and storage require long-lasting changes in memory-related neuronal circuits. Recent evidence indicates that DNA methylation may serve as a contributing mechanism in memory formation and storage. These emerging findings suggest a role for an epigenetic mechanism in learning and long-term memory maintenance and raise apparent conundrums and questions. For example, it is unclear how DNA methylation might be reversed during the formation of a memory, how changes in DNA methylation alter neuronal function to promote memory formation, and how DNA methylation patterns differ between neuronal structures to enable both consolidation and storage of memories. Here we evaluate the existing evidence supporting a role for DNA methylation in memory, discuss how DNA methylation may affect genetic and neuronal function to contribute to behavior, propose several future directions for the emerging subfield of neuroepigenetics, and begin to address some of the broader implications of this work.

At a glance


  1. DNA methylation.
    Figure 1: DNA methylation.

    (a) Inside a cell nucleus, DNA is wrapped tightly around an octamer of highly basic histone proteins to form chromatin. Epigenetic modifications can occur at histone tails or directly at DNA via (b) DNA methylation occurs at cytosine bases when a methyl group is added at the 5′ position on the pyrimidine ring by a DNMT. (c) Two types of DNMTs initiate De novo DNMTs methylate previously nonmethylated cytosines, whereas maintenance DNMTs methylate hemi-methylated DNA at the complementary strand.

  2. Potential mechanism for demethylation of methylated DNA.
    Figure 2: Potential mechanism for demethylation of methylated DNA.

    Methylated DNA is deaminated and converted to thymine. Base or nucleotide excision repair processes are then able to replace thymine with unmethylated cytosine. It is unclear how this potential mechanism would affect methylation status on the complementary DNA strand.

  3. Putative actions of cell-wide DNA methylation changes on neuronal function.
    Figure 3: Putative actions of cell-wide DNA methylation changes on neuronal function.

    Changes in DNA methylation could induce a state change (left) that alters responsivity to existing inputs and acts permissively to enable other long-term changes that are ultimately responsible for memory. Altered patterns of DNA methylation could also directly or indirectly alter gene expression and contribute to changes in synaptic strength that are thought to underlie the formation and maintenance of memories (center). Alternatively, changes in methylation status in a cell may act to render it aplastic, in effect stabilizing the current synaptic weights and responsivity (right). Critically, these changes may occur in different brain regions or at different time points as part of the overall process of learning, memory consolidation and memory maintenance. It is important to note that the changes in DNA methylation driving altered neuronal function are likely to occur at a small subset of the total methylation sites in the cell so that the overall neuronal phenotype is preserved. It also is worth considering that because the methyl-DNA binding proteins do not effectively recognize hemi-methylated DNA, hemi-demethylation of DNA is likely to be just as effective as double-stranded demethylation at triggering functional changes in the neuron.


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  1. Department of Neurobiology and Evelyn F. McKnight Brain Institute, University of Alabama at Birmingham, Birmingham, Alabama, USA.

    • Jeremy J Day &
    • J David Sweatt

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