DNA methylation impacts on learning and memory in aging

Abstract

Learning and memory are two of the fundamental cognitive functions that confer us the ability to accumulate knowledge from our experiences. Although we use these two mental skills continuously, understanding the molecular basis of learning and memory is very challenging. Methylation modification of DNA is an epigenetic mechanism that plays important roles in regulating gene expression, which is one of the key processes underlying the functions of cells including neurons. Interestingly, a genome-wide decline in DNA methylation occurs in the brain during normal aging, which coincides with a functional decline in learning and memory with age. It has been speculated that DNA methylation in neurons might be involved in memory coding. However, direct evidence supporting the role of DNA methylation in memory formation is still under investigation. This particular function of DNA methylation has not drawn wide attention despite several important studies that have provided supportive evidence for the epigenetic control of memory formation. To facilitate further exploration of the epigenetic basis of memory function, we will review existing studies on DNA methylation that are related to the development and function of the nervous system. We will focus on studies illustrating how DNA methylation regulates neural activities and memory formation via the control of gene expression in neurons, and relate these studies to various age-related neurological disorders that affect cognitive functions.

Fig. 1

(A) A hypothetical model depicts that methylation changes of neuronal DNA in response to an external stimulus can alter the epigenotype of the neuron, which subsequently modulates the expression of a subset of genes encoding key neuronal proteins such as neurotransmitters/receptors. Such changes in neurotransmitter/receptor levels will in turn alter the neuron’s synaptic strength with its associated neurons, leading to a modified response upon exposure to the same stimulus later; (B and C) models illustrating methylation-dependent regulation of the activities of neuronal genes such as BDNF in neurons. In addition to the methylation status of the promoter per se, posttranslational modification of the MeCP2 protein alters how the MeCP2-associated transcription repressor complex reads the methylation codes to determine the expression status of key genes in response to external stimuli. C: Unmethylated cytosine; mC: methylated cytosine.

Fig. 2

(A) A simplified map of one-carbon metabolism and biological DNA methylation. MET, methionine; SAM, S-adenosylmethionine; SAH, S-adenosylhomocysteine; HCY: homocysteine. (B) Expected effects of folate/B12 or choline deficiency include: (1) impairing the conversion of HCY into MET (and resulting in a low level of SAM); (2) increasing the level of HCY; (3) reversing the reaction dynamics between HCY and SAH that favors SAH synthesis. These effects will eventually lead to defective genomic methylation, whereas sufficient folate/B12 or choline supplies can maintain effective genomic methylation.