Methylation and Memory Formation

Contributed by David L. Molfese, Ph.D.

The methylation of DNA and histones is a dynamic process catalyzed by a family of enzymes called DNA methyltransferases (DNMTs). In vertebrates, 60-90% of cytosine-phosphate-guanine (CpG) DNA sites are methylated (1), indicating the importance of this mechanism to the cell. DNA methylation plays a major role in the regulation of gene expression by silencing genes through conversion of cytosine to 5-methylcytosine (2, 3). This conversion interferes with RNA polymerase initiation (4).

The methylation of DNA and histone proteins has been implicated in learning and memory, addiction, and depression. For example, in the hippocampus, DNA methylation is dynamically regulated during contextual fear conditioning in rats and mice, where blocking DNA methyltransferases (DNMTs) inhibits memory formation (5). Additionally, DNA methylation plays a role in synaptic plasticity. In field electrophysiology experiments, blocking DNMTs with Zebularine or 5-aza-2-deoxycytidine impairs induction of long-term potentiation at Schaffer collateral synapses (6).

Interestingly, DNA methylation can be influenced by environmental stimulation. For example, the glucocorticoid receptor promoter is methylated during maternal licking and grooming behavior in rodents; however, in cases of abusive or inattentive maternal care, the glucocorticoid receptor promoter is not methylated (7).

In addition to being involved in the direct methylation of DNA, DNMTs have also been found to interact with both histone aceytl- and methyltransferases (8). Altered histone acetylation and methylation have been linked to cancer (9-13), schizophrenia (14), depression (15), and addiction (16). Gene regulation through methylation of DNA and histone modifications plays an important role in cellular function and animal behavior and thus should be considered during both in vitro and in vivo assays of gene expression.

References

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15. Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action. (2006).
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