With the support of a NARSAD Distinguished Investigator Grant, a team of neuroscientists at the Johns Hopkins University School of Medicine has discovered a biological mechanism that helps explain the long mysterious relationship between early-life stress and the onset of severe mental illness.
In a study published in the journal Science, Brain & Behavior Research Foundation Scientific Council Member and NARSAD Grantee Akira Sawa, M.D., Ph.D. and colleagues show that when mice with a genetic predisposition to mental illness experience stress as adolescents they are more likely to go on to develop severe mental illnesses such as schizophrenia and depression. The mouse model mimics a form of stress—social isolation—during the mouse equivalent of human adolescence, a critical period for brain development.
In one part of their work, the team of researchers discovered that healthy young mice, when held in isolation from their parents during adolescence, were able to reintegrate without much difficulty once the isolation period was ended. They developed no related behavioral abnormalities. Not so for “high-risk” mice, harboring a known genetic predisposition to adult illness. They failed to reintegrate and developed symptoms as adult mice—such as hyperactivity in response to psychostimulants and lack of interest in certain pleasurable activities—that are analogs of severe behavioral disorders in people.
Examinations of the affected mice revealed the absence of robust anatomical abnormalities in the brain (in the ventricles and frontal cortex) known to accompany the corresponding behavioral changes. This turned the attention of Dr. Sawa’s team to changes in the activity of brain chemicals, specifically the neurotransmitter dopamine. In mice with isolation-induced behavioral changes, levels of dopamine were found to be well below normal; the same mice also had above-normal levels of corticosterone, the main hormone in the brain that responds to elevated stress.
Dr. Sawa’s team connected these dots. By blocking corticosterone by giving affected animals doses of the drug RU-486 (better known as the “morning-after” birth control drug), dopamine levels returned to normal and behavioral symptoms vanished. This led them to discover a so-called epigenetic mechanism—the addition of a molecular “tag” to DNA in a specific gene—that alters gene expression and reduces dopamine production.
"We've shown in mice that stress in adolescence can affect the expression of a gene that codes for a key neurotransmitter related to mental function and psychiatric illness,” explains Dr. Sawa. While many genes are believed to be involved in the development of mental illness, we continue to learn more about how environmental factors are critically important to the process."
According to Dr. Sawa, the new study highlights the need for better preventive care in teenagers who have mental illness in their families, and also sheds light on the cascade of events that occurs when cortisol levels are elevated, furthering researchers’ ability to develop new treatments with fewer side effects than RU486 has.
Akira Sawa, M.D., Ph.D.
Professor, Psychiatry and Behavioral Sciences, Director of the Schizophrenia Center, Johns Hopkins University;
2002, 2004 NARSAD Young Investigator Grantee,
2011 NARSAD Distinguished Investigator Grantee,
Scientific Council Member