DNA methylation studies in mouse models of depression: a systematic review

Major depression (MD) is caused by both genetic and environmental factors. Epigenetic mechanisms, particularly DNA methylation (5mC) and hydroxymethylation (5hmC), are thought to mediate gene – environment interactions. However, findings in mouse models remain dispersed. This review evaluates the studies on 5mC and 5hmC in mouse models of depression. We systematically searched PubMed, Scopus, and Web of Science using terms related to 5mC/5hmC, depression, and mouse, until December 2024. We grouped the articles as candidate, global, cellular, and comprehensive studies and summarized the findings accordingly. Sixty-eight studies met inclusion criteria. The main findings were environmental models, especially chronic stress paradigms, which were most frequently used to induce depression models. Candidate gene studies focused on Bdnf and Nr3c1, while global and cellular assays revealed both regional and widespread 5mC/5hmC changes. Genome-wide approaches revealed that epigenetic changes are not limited to isolated loci rather affect broad genomic regions involved in neural development and plasticity. This review provides a comprehensive summary of existing research on epigenetic changes in terms of DNA methylation in mouse models of depression. Broader application of standardized, integrative, and cell-type-specific approaches is needed to fully elucidate the role of epigenetic regulation in the pathology of MD. Depression is a major mental health problem, often triggered by stress. Researchers have found that changes to DNA activity – without changing the DNA itself – may play a role. These changes, known as DNA methylation, can affect how genes work. This review looked at 68 studies using mice with depression-like behaviors. Many showed that stress changes DNA methylation in brain regions linked to mood. Key genes involved in stress response and brain function were often affected. The findings suggest that stress may leave lasting marks on DNA, helping explain how depression develops. More consistent research methods are needed to fully understand these effects.