4.1.5: Epigenetic Mechanisms in Psychological Disorders

Pictured above is a chromatin, the spiral-looking macromolecule involved in depression. [Image: Zephyris, https://goo.gl/6DBQ1g, CC BY-SA 3.0, https://goo.gl/eLCn2O]

Epigenome-wide studies have identified several dozen sites with DNA methylation alterations in genes involved in brain development and neurotransmitter pathways, which had previously been associated with mental illness (Mill et al., 2008). These disorders are complex and typically start at a young age and cause lifelong disability. Often, limited benefits from treatment make these diseases some of the most burdensome disorders for individuals, families, and society. It has become evident that the efforts to identify the primary causes of complex psychiatric disorders may significantly benefit from studies linking environmental effects with changes observed within the individual cells.

Epigenetic events that alter chromatin structure to regulate programs of gene expression have been associated with depression-related behavior and action of antidepressant medications, with increasing evidence for similar mechanisms occurring in post-mortem brains of depressed individuals. In mice, social avoidance resulted in decreased expression of hippocampal genes important in mediating depressive responses (Tsankova et al., 2006). Similarly, chronic social defeat stress was found to decrease expression of genes implicated in normal emotion processing (Lutter et al., 2008). Consistent with these findings, levels of histone markers of increased gene expression were down regulated in human post-mortem brain samples from individuals with a history of clinical depression (Covington et al., 2009).

Administration of antidepressants increased histone markers of increased gene expression and reversed the gene repression induced by defeat stress (Lee, Wynder, Schmidt, McCafferty, & Shiekhattar, 2006; Tsankova et al., 2006; Wilkinson et al., 2009). These results provide support for the use of HDAC inhibitors against depression. Accordingly, several HDAC inhibitors have been found to exert antidepressant effects by each modifying distinct cellular targets (Cassel et al., 2006; Schroeder, Lin, Crusio, & Akbarian, 2007).

There is also increasing evidence that aberrant gene expression resulting from altered epigenetic regulation is associated with the pathophysiology of suicide (McGowan et al., 2008; Poulter et al., 2008). Thus, it is tempting to speculate that there is an epigenetically determined reduced capacity for gene expression, which is required for learning and memory, in the brains of suicide victims.

Epigenetic strategy to understanding gene-environment interactions

Although there is some evidence that a dysfunctional upbringing can increase one’s likelihood for schizophrenia (an epigenetically inherited disease), some people who have both the predisposition and the stressful environment never develop the mental illness. [Image: Steve White, CC0 Public Domain, https://goo.gl/m25gce]

While the cellular and molecular mechanisms that influence on physical and mental health have long been a central focus of neuroscience, only in recent years has attention turned to the epigenetic mechanisms behind the dynamic changes in gene expression responsible for normal cognitive function and increased risk for mental illness. The links between early environment and epigenetic modifications suggest a mechanism underlying gene-environment interactions. Early environmental adversity alone is not a sufficient cause of mental illness, because many individuals with a history of severe childhood maltreatment or trauma remain healthy. It is increasingly becoming evident that inherited differences in the segments of specific genes may moderate the effects of adversity and determine who is sensitive and who is resilient through a gene-environment interplay. Genes such as the glucocorticoid receptor appear to moderate the effects of childhood adversity on mental illness. Remarkably, epigenetic DNA modifications have been identified that may underlie the long-lasting effects of environment on biological functions. This new epigenetic research is pointing to a new strategy to understanding gene-environment interactions.

The next decade of research will show if this potential can be exploited in the development of new therapeutic options that may alter the traces that early environment leaves on the genome. However, as discussed in this module, the epigenome is not static and can be molded by developmental signals, environmental perturbations, and disease states, which present an experimental challenge in the search for epigenetic risk factors in psychological disorders (Rakyan, Down, Balding, & Beck, 2011). The sample size and epigenomic assay required is dependent on the number of tissues affected, as well as the type and distribution of epigenetic modifications. The combination of genetic association maps studies with epigenome-wide developmental studies may help identify novel molecular mechanisms to explain features of inheritance of personality traits and transform our understanding of the biological basis of psychology. Importantly, these epigenetic studies may lead to identification of novel therapeutic targets and enable the development of improved strategies for early diagnosis, prevention, and better treatment of psychological and behavioral disorders.

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