Figure 2

DNA methylation in learning and memory. Upper: One neuron (central green circle) has a number of connections with other neurons (peripheral circles). Lower: Each small circle represents a CpG site in a regulatory element of the gene. Filled circles indicate methylated CpGs and the white circles unmethylated CpGs. When the animal has a new experience ("Memory formation" state), some connections are activated (red dashed lines). Transient waves of gene upregulation or downregulation are required for memory formation and could be mediated by temporal modifications of DNA methylation. Memory suppressor genes (Gene B), such as PP1, are transcriptionally downregulated through DNA methylation, and plasticity-inducing genes, such as BDNF or reelin (Gene A), are upregulated with DNA demethylation. The methylation states of these genes are restored to the baseline level after memory consolidation. When the memory has been stabilized ("Memory maintenance" state), the neurons exhibit an altered profile of connection strength (compared to "Before learning" state in upper panel). We expect that the gene expression patterns in neurons need to be different from those before learning in order to maintain this modified combination of connection strengths. Maintaining this altered gene expression pattern might involve a stable change in DNA methylation. Calcineurin is a known example for Gene D that is increased in cytosine methylation and decreased in mRNA level. However, Gene C with decreased methylation and increased mRNA level that is associated with learning and memory has not been discovered in adult animals.