Epigenetic mechanisms of depression and antidepressant action

Abstract

Epigenetic mechanisms, which control chromatin structure and function, mediate changes in gene expression that occur in response to diverse stimuli. Recent research has established that environmental events and behavioral experience induce epigenetic changes at particular gene loci and that these changes help shape neuronal plasticity and function and hence behavior. Some of these changes can be stable and can even persist for a lifetime. Increasing evidence supports the hypothesis that aberrations in chromatin remodeling and subsequent effects on gene expression within limbic brain regions contribute to the pathogenesis of depression and other stress-related disorders such as post-traumatic stress disorder and other anxiety syndromes. Likewise, the gradually developing but persistent therapeutic effects of antidepressant medications may be achieved in part via epigenetic mechanisms. This review discusses recent advances in our understanding of the epigenetic regulation of stress-related disorders and focuses on three distinct aspects of stress-induced epigenetic pathology: the effects of stress and antidepressant treatment during adulthood, the lifelong effects of early-life stress on subsequent stress vulnerability, and the possible transgenerational transmission of stress-induced abnormalities.

Figure 1. Effect of stress on DNA methylation and gene expression

Cartoon of sagittal section of rodent brain depicts several inter-connected regions that have been implicated in stress responses (top). Table (bottom) lists the small number of specific genes whose methylation has been shown to date to be altered by stress, the brain regions in which this regulation occurs, and the type of stress involved. Transcriptional mechanisms associated with such altered DNA methylation are listed under Associated Mechanisms. Arrows indicate increase (red) or decrease (green) in gene expression (left) or methylation (right). References are in superscript. Hipp, hippocampus; PFC, prefrontal cortex; PVN, paraventricular nucleus of hypothalamus; NAc, nucleus accumbens; AMY, amygdala; VTA, ventral tegmental area; DR, dorsal raphe; LC, locus coeruleus; Sus, susceptible; Res, resilient.

Figure 2. Chromatin modifications regulated by stress or antidepressant treatment

Illustration (top) indicates histone octomers (pink) in heterochromatin (left) and euchromatin (right), along with associated proteins and histone tail/DNA modifications. A, acetylation; P, phosphorylation; square M, histone methylation; circle M, DNA methylation. Table (bottom) lists histone tail modifications of specific residues—depicted on the expanded histone tail illustration (left)—that are regulated by various stress paradigms or antidepressant treatments within the indicated brain regions. Arrows indicate an increase (red) or decrease (green) in specific modifications. References are in superscript. HDAC, histone deacetylase; HMT, histone methyltransferase; HAT, histone acetyltransferase; Pol II, RNA polymerase II; Trans. Factor, transcription factor.

Figure 3. Enhanced Vulnerability to stress via cocaine-Induced priming of BDNF signaling in NAc

Repeated cocaine increases vulnerability to the depressive-like effects of social defeat stress via priming BDNF signaling through Ras induction in NAc. Under control conditions (left view), BDNF activation of TrkB signaling is limited. However, after repeated cocaine (right view), BDNF-TrkB signaling is elevated in NAc, causing enhanced phosphorylation and activity of downstream-signaling mediators including CREB. This cocaine-initiated maladaptive response occurs not only through increased BDNF signaling in NAc but also through increased Ras expression as a result of decreased G9a binding, and decreased H3K9me2, at the H-Ras1 gene promoter. Chronic stress is associated with similar adaptations in this brain region. Ras also appears to be a target for CREB, creating a positive feed-forward loop, promoting CREB activation and Ras expression as well as depressive-like behavior. From .

Figure 4. Regulation of H3K9me2 and phospho-CREB (pCREB) binding in NAc after chronic social defeat stress

A. The heatmaps show that, for both marks, the large majority of changes (red, up; green, down) seen in susceptible mice are not seen after chronic imipramine; as well, most changes observed in susceptible mice are not seen in resilient mice and vice versa. Note the lower bars in each heatmap are normalized to the upper bars, meaning that green would depict reversal of a red change, not a change in the opposite direction. B. The Venn diagrams show the appreciable overlap between apparent mechanisms of imipramine and of resilience. From .

Figure 5. Long-term epigenetic effect of maternal care

Studies in rats have shown that epigenetics can influence maternal behavior and that this effect can be passed from one generation to the next by acting on the pup’s brain alone, without altering germ cells. When pups are born, genes involved in regulating the animals’ responses to stress are differentially methylated, which enhances sensitivity to stress. If the pups are raised by a mother that displays high levels of grooming behavior, many of these methyl marks are removed, leaving the animals less responsive to stress. When these pups mature, they, too, will be more attentive mothers. If the pups, however, are raised by a mother that displays low levels of grooming, their genes will gain methyl marks. They grow up to be more stress responsive and display lower grooming levels toward their own pups. From .

Figure 6. Contribution of epigenetic modifications throughout life cycle

Environmental challenges, such as stress, have been associated with several short- and long-term chromatin modifications in the brain affecting neural development and function. Gametes and primordial germ cells are also sensitive to stress and might carry epigenetic transformation through subsequent generations. The development of germ cells is characterized by the genome-wide demethylation of DNA in gametes and the establishment of parental chromatin marks required for genomic imprinting. Following fertilization, there is another genome-wide DNA demethylation phase. However, some epigenetic marks escape such reprogramming (imprinted genes, DNA methylation at specific location, some histone post-translational modifications). Moreover, thousands of non-coding RNAs present in the gametes could transmit their information and potentially affect the cellular phenotype in a non-genomic manner. Modified with permission from .