Epigenetic Alterations in DNA and Histone Modifications Caused by Depression and Antidepressant Drugs: Lessons from the Rodent Models.

ABSTRACT

Epigenetic modifications regulate chromatin folding and function. Epigenetic mechanisms regulate transcription mediating effects of various stimuli on gene expression. These mechanisms are involved in transcriptional control in various physiological and pathological conditions including neuropsychiatric disorders and behavioral abnormalities such as depression. In rodents, exposure to chronic social stress was shown to induce behavioral impairments and memory/learning deficits that resemble depressive-like phenotype in humans. The rodent models of chronic stress were widely used to study molecular mechanisms of depression. In these models, early exposure to chronic stress such as prenatal or postnatal stress induces long-term hyperactive stress responses, behavioral abnormalities, and functional impairments in brain function that persist in adulthood. Furthermore, these alterations can be transmitted to offspring of chronically stressed animals across several generations. Molecular studies in animal models showed that chronic stress induces stable epigenetic changes in specific brain regions, primarily in the limbic system. These changes lead to long-lasting abnormalities in behavior that persist in adulthood and can be transmitted to offspring. Treatment with epigenetically active antidepressants disrupts the abnormal stress-induced epigenetic programming and provides epigenetic patterns that resemble epigenetic background of stress resilient individuals.