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.

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 DNA methylation. b, DNA methylation occurs at cytosine bases when a methyl group is added at the 5' position on the pyrimidine ring by a DNA methyltransferase (DNMT). c, Two types of DNMTs initiate DNA methylation. De novo DNMTs methylate previously non-methylated cytosines, whereas maintenance DNMTs methylate hemi-methylated DNA at the complementary strand.

Putative actions of cell-wide DNA methylation changes on neuronal function. Changes in DNA methylation could induce a state change (left panel) which alters responsivity to existing inputs and acts permissively to enable other long-term changes which 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 panel). Alternatively, changes in methylation status within a cell may act to render it aplastic, in effect stabilizing the current synaptic weights and responsivity (right panel). 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, in order that the overall neuronal phenotype be 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 just as effective as doublestranded demethylation in triggering functional changes in the neuron.