Studies Identify Subtle Genetic Changes’ Risk for Mental Disorders; May Lead to Targets for New, Better, Therapies

May 5, 2008 • Science Update

WASHINGTON, DC, May 5 — Epigenetics — the examination of how environmental factors like diet, stress, and post-natal maternal behavior can change gene function without altering DNA sequence — plays a major role in depression and in the actions of antidepressant medications. New studies in the field are revealing new molecular targets for better therapies for depression, scientists say.

They spoke at a press conference today following a National Institute of Mental Health (NIMH)-sponsored symposium on epigenetics during the American Psychiatric Association Annual Meeting here. NIMH is a part of the National Institutes of Health.

"The mechanisms that precipitate depression, such as stress, are incompletely understood," says Eric Nestler, MD, PhD, of The University of Texas Southwestern Medical School in Dallas, and organizer of the symposium. "One mystery of the disease is its long-lasting nature and delayed response to antidepressant treatment. This persistence is thought to be influenced by slowly developing but stable adaptations, which might include epigenetic regulation."

Unlike mutations, epigenetic changes aren't variations in the sequences of building blocks that make up the DNA in a gene. The genes remain stable, but environmental factors — such as stress, diet and maternal care received early in life — act on the supporting structures of DNA, such as chromatin, molecules that package genes into chromosomes. Certain chemical reactions can unravel the chromatin, causing the DNA code that comprises a gene to be exposed for longer or shorter periods of time, essentially turning the gene on or off, and allowing it to produce more or less protein. This change in protein production, in turn, can affect physical and behavioral traits, and can be passed on from one cell to the next as they multiply within an organism, and even from parents to children.

Depression is a common, chronic and debilitating disease that affects more than 15 million Americans. Although many patients benefit from antidepressant medications, psychotherapy and other treatments, not all patients respond to treatment. This underscores the need for more effective agents.

The recent epigenetic studies in depression are a high priority for the field because they allow characterization of important changes in chromatin mechanisms that occur in the brain of animal models of depression during antidepressant treatment, and in studies of human postmortem brain tissue.

Subtle Changes Traced to Depression-Like Symptoms

At a molecular level, Nestler* and his colleagues have found changes in chromatin remodeling in particular genes in brain areas known as the nucleus accumbens and hippocampus in response to chronic social stress.

"In both brain regions, we have been able to directly relate these chromatin changes to some of the behavioral abnormalities observed," says Nestler. In animal models of chronic stress, Nestler and his colleagues manipulated chromatin in these brain areas in ways that produced antidepressant-like effects.

This work provides new insight into the molecular mechanisms by which chronic stress produces lasting changes in specific brain areas to cause depression-like symptoms, says Nestler. The findings also suggest new leads for the development of new antidepressant treatments.

Modifications Enhance Therapeutic Response

In other studies, Schahram Akbarian, MD, PhD, and his colleagues at the University of Massachusetts Medical School in Worcester, MA, are studying changes in methylation, a type of chemical modification of the DNA and of histones, the protein "backbone" of chromatin.

"We found that these chemical modifications in brain chromatin are dynamically regulated from the perinatal period to old age, and could be involved in epigenetic control of gene expression, including genes for brain-derived neurotrophic factor and others implicated in mood and anxiety spectrum disorders," says Akbarian.

His epigenetic findings may have direct implications for the design of novel antidepressant treatment strategies. Preliminary findings from studies in mice in Akbarian's laboratory indicate that chemical modification of epigenetic-related factors could enhance the therapeutic response to frequently prescribed antidepressant drugs such as fluoxetine (Prozac) or monoamine oxidase inhibitors. These findings also suggest that a better understanding of epigenetic and other "non-genetic" mechanisms operating in the human and animal brain may, in the future, lead to better treatment options for patients diagnosed with a major mood disorder.

Maternal Care Affects Behavior

Michael Meaney, PhD, of McGill University in Montreal, reports how early maternal separation alters the methylation state of specific genes in the rodent hippocampus, and triggers long-lasting behavioral effects.

Meaney and his colleagues have found that differences in maternal care, such as grooming and licking, can change how rat pups' behavioral and hormonal response to stress develops. This leads to persistent lifelong changes in the pups' response to stress and how they process information about stressors.

"This may reveal experience-dependent adaptability in the chemistry of the DNA and chromatin structure," Meaney says.

^*Some of Nestler's work is supported by a grant from AstraZeneca.