Researchers in John Hopkins working with mice found a
link between elevated levels of a stress hormone in adolescence - a
critical time for brain development - and genetic changes that, in young
adulthood, cause severe mental illness in those predisposed to it.
The findings, reported in the journal Science, could
have wide-reaching implications in both the prevention and treatment of
schizophrenia, severe depression and other mental illnesses.
"We
have discovered a mechanism for how environmental factors, such as
stress hormones, can affect the brain’s physiology and bring about
mental illness," says study leader Akira Sawa, M.D., Ph.D., a professor
of psychiatry and behavioral sciences at the Johns Hopkins University
School of Medicine. "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. While many genes are
believed to be involved in the development of mental illness, my gut
feeling is environmental factors are critically important to the
process."
Sawa, director of the Johns Hopkins
Schizophrenia Center, and his team set out to simulate social isolation
associated with the difficult years of adolescents in human teens. They
found that isolating healthy mice from other mice for three weeks during
the equivalent of rodent adolescence had no effect on their behavior.
But, when mice known to have a genetic predisposition to characteristics
of mental illness were similarly isolated, they exhibited behaviors
associated with mental illness, such as hyperactivity. They also failed
to swim when put in a pool, an indirect correlate of human depression.
When the isolated mice with genetic risk factors for mental illness were
returned to group housing with other mice, they continued to exhibit
these abnormal behaviors, a finding that suggests the effects of
isolation lasted into the equivalent of adulthood.
"Genetic
risk factors in these experiments were necessary, but not sufficient,
to cause behaviors associated with mental illness in mice," Sawa says.
"Only the addition of the external stressor - in this case, excess
cortisol related to social isolation - was enough to bring about
dramatic behavior changes."
The investigators not
only found that the "mentally ill" mice had elevated levels of cortisol,
known as the stress hormone because it's secreted in higher levels
during the body’s fight-or-flight response. They also found that these
mice had significantly lower levels of the neurotransmitter dopamine in a
specific region of the brain involved in higher brain function, such as
emotional control and cognition. Changes in dopamine in the brains of
patients with schizophrenia, depression and mood disorders have been
suggested in clinical studies, but the mechanism for the clinical impact
remains elusive.
To determine whether cortisol
levels were influencing dopamine levels in the brain and adult
behavioral patterns in the abnormal mice, the investigators gave them a
compound called RU486, known to block cells from receiving cortisol.
(The drug is commonly known as the "abortion pill.") All symptoms
subsided. RU486 has also been studied in a clinical trial of people with
difficult-to-treat psychotic depression, showing some benefits. "The
mice swam longer, they were less hyper and their dopamine levels
normalized," Sawa says.
To shed light on how and why the mice got better, Sawa and his team studied the gene tyrosine hydroxylase (Th)
and found an epigenetic change, essentially the addition of a methyl
group to one of the gene’s DNA letters, limiting the gene’s ability to
do its job, which is to create an enzyme that regulates dopamine levels.
Without a fully functioning Th, dopamine levels are abnormally low.
Scientists
have long studied gene mutations, permanent DNA changes that can tweak
the normal function of a particular gene. But epigenetic alterations do
not change the actual letters of the DNA sequence. Instead, they add a
chemical group like methyl that can affect the function of the DNA.
These changes can be transient, whereas genetic mutations are permanent.
Sawa
says the new study points to the need to think about better preventive
care in teenagers who have mental illness in their families, including
efforts to protect them from social stressors, such as neglect.
Meanwhile, by understanding the cascade of events that occurs when
cortisol levels are elevated, researchers may be able to develop new
compounds to target tough-to-treat psychiatric disorders with fewer side
effects than RU486 has.
Other Johns Hopkins
researchers who contributed to this study include Minae Niwa, Ph.D.;
Hanna Jaaro-Peled, Ph.D.; Saurav Seshadri, Ph.D.; Nicola G. Cascella,
M.D.; and Shin-ichi Kano, M.D., Ph.D.
This research
was supported by grants from the National Institutes of Health’s
National Institute of Mental Health (MH-084018, MH-094268, MH-069853,
MH-085226, MH-088753, MH-092443, K99MH-094408), Stanley, RUSK, S-R, the
Brain & Behavior Research Foundation (formerly NARSAD), the Maryland
Stem Cell Research Fund and the Japan Society for the Promotion of
Science.
