Genes and Environment Combine to Bring on Mental Illness

Koki Ito, a postdoctoral researcher at Johns Hopkins University, inserts DNA containing a mutated DISC1 gene into a mouse fetus.

Schizophrenia and other serious mental illnesses typically manifest during young adulthood or late adolescence. But what causes a person to develop these diseases? Are there triggers? And if we knew what they were, could the illness be prevented?

It’s been known that chronic stress can increase a person’s chances of developing a neuropsychiatric disorder if already predisposed by the genes inherited. Immigrants, for example, are collectively more likely to develop the disease.

“Being an immigrant can bring on chronic stress,” said Akira Sawa, director of the Johns Hopkins Schizophrenia Center. “There’s difficulty adjusting to a new language… and it’s usually thought that a person might be isolated from the core of their community.”

A study by Sawa’s team that appeared in the journal Science on Jan. 18 takes that knowledge a step farther. Their research shows that chronic stress during adolescence influences the function of a gene known to place people at risk for developing several types of mental illness. The finding also highlights the importance in mental illness of epigenetics, the study of how people’s experience and environment affect the function of their genes.

In the paper, researchers describe a mechanism for why this happens, along with a possible drug that might help prevent the onset of the disease by targeting the stress system.

A group of mice in the study were socially isolated to mimic possible stress during adolescence. (Solitary cage confinement is a powerful stressor for a mouse.) Some of these mice were also bred to have a mutated form of a gene called DISC1. This gene has been linked to schizophrenia and other mood disorders.

Since animals can’t tell you how they’re feeling, scientists rely on behaviors thought to mimic characteristics of psychiatric disorders. In this case, they used three models. A forced swim test is a common model used to study depression. Rats and mice are notoriously lousy swimmers, and when the animals are dropped into a container of water, they struggle to keep their heads above the surface and breathe. How long the animal tries to swim — or essentially fights for its life — is considered a good indicator for the degree of depression. The more time it takes before an animal gives up, the less “depressed” it is.

Research showed that the DISC1 mice that had been stressed were twice as likely to give up on the swim test as those that had not. In two other tests, one in which mice were exposed to recurring loud noises, and another in which they were given methamphetamines, the stressed mice also fared substantially worse. Both models mimic some characteristics of psychosis and schizophrenia — trouble filtering out multiple stimuli and hypersensitivity to amphetamine-like stimulants. This effect was not seen in the DISC1 mice without stress nor any of the mice without the DISC1 gene. In other words, animals with both the mutated gene and the stress were highly likely to develop characteristics of mental illness.

What’s more, the researchers found that these vulnerabilities caused by stress continued into the animal’s adult life.

The team also found that the “mentally ill” mice had elevated levels of the hormone cortisol, which is secreted during times of stress and low levels of the neurotransmitter dopamine in the brain’s prefrontal cortex, an area involved in emotional control and cognition.

Here’s where it gets even more interesting. Sawa wanted to know whether the dopamine and cortisol effects were linked, so he gave them a drug called RU486. RU486 is commonly known as the abortion pill. It interferes with a woman’s progesterone levels, a hormone that’s critical in the early stages of pregnancy. But the team discovered that RU486 also blocks dopamine cells in the brain from receiving the stress hormone, cortisol.

Cortisol floats inside our blood, and dopamine neurons, it turns out, have a specific receptor that recognizes the hormone.

An important aspect of epigenetics involves looking at the biological mechanisms underlying how a gene functions. One such mechanism is DNA methylation, which acts like a gas or brake pedal, turning a gene’s expression on or off.

In the case of the dopamine neurons, the cortisol released by stress was affecting the methylation of a gene that regulates the dopamine system. When this gene was turned off or not fully functioning, the dopamine levels became abnormally low. The RU486 drug was blocking the cortisol-dopamine interaction, and it thus normalized the dopamine.

And indeed, for the animals that received the drug, the symptoms of mental illness subsided, said Minae Niwa, the study’s lead author. They swam longer in the swim test, showed fewer “mental illness” symptoms, and their dopamine levels returned to normal.

Bruce McEwen, a professor at Rockefeller University and an expert on the role of stress on the brain, said in an email that the implications for mental illness are indirect since the study is on mice and not children. But, added McEwen, who mentioned the paper in a Perspective article in last week’s issue of Science, “it’s nevertheless of interest because of the interactive nature of genes with experiential factors and the role of cortisol. It is epigenetics that is now a major focus of understanding vulnerability for mental health disorders.”

Psychotic depression is a uniquely difficult illness to treat, Sawa said. Existing treatments often involve combining antipsychotics and antidepressants, but this combination is flawed. Resistance to the treatment is common; so are side effects.

RU486 has also proven to be imperfect as a treatment and has severe side effects. But understanding the mechanism of how it works could help scientists develop future novel drugs for psychotic depression.

The research, Sawa added, also highlights the potential of protecting teens, especially those with a family history of mental illness, from stress and neglect. Lifestyle adjustments, if achieved in time, could possibly help prevent onset of the disease as well as long-term problems.

“We’ve shown one mechanism for how adolescent stressors lead to long-term brain dysfunction in adults,” Sawa said. “We may have a way to overcome such long-term effects biologically…or this may result in a way to intervene in their lifestyle.”

Photo credit: Minae Niwa, lead author of the study, explains the animal experiments at the lab.