Activity-dependent DNA methylation and demethylation: epigenetic regulators of learning and memory

Learning and memory are fundamental cognitive processes that rely on activity-dependent epigenetic mechanisms to shape synaptic and neuronal plasticity. Among these, DNA methylation and demethylation have emerged as pivotal regulators that convert transient neural activity into enduring transcriptional programs. In mammals, DNA methylation marks include 5-methylcytosine (5mC) as well as the less well-established N6-methyladenine (6mA) and the more enigmatic N4-methylcytosine (4mC). Compared with 5mC, the abundance, genomic distribution, and regulatory role of 6mA and 4mC remain incompletely defined, partly due to low abundance and technical challenges, yet these non-canonical marks may provide an additional regulatory layer in specific biological contexts. Accordingly, this review focuses on the best-characterized pathway in the nervous system, 5mC and its activity-regulated oxidative turnover. This system comprises a dynamic spectrum of cytosine modifications, including 5mC, 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC), orchestrated by distinct enzyme families such as DNMTs, TETs, and TDG. We review current insights about how these regulators shape activity-induced gene expression programs underlying learning and memory, and we discuss how dysregulated DNA (de) methylation contributes to impaired transcriptional control and cognitive decline in neurodegenerative diseases, particularly Alzheimer's disease. Finally, we highlight recent advances in high-resolution mapping technologies for DNA modifications, which are expanding our ability to resolve cell type- and locus-specific epigenetic dynamics in the brain. A deeper understanding of these pathways may inform targeted strategies to preserve or restore cognitive function in neurological disorders.