|How Schizophrenia Develops: Major Clues Discovered
Findings may lead to better medications to correct gene-related
Schizophrenia may occur, in part, because of a problem in an intermittent
on/off switch for a gene involved in making a key chemical messenger
in the brain, scientists have found in a study of human brain tissue.
The researchers found that the gene is turned on at increasingly
high rates during normal development of the prefrontal cortex,
the part of the brain involved in higher functions like thinking
and decision-making — but that this normal increase may not
occur in people with schizophrenia.
The study was funded by the National Institutes of Health's National
Institute of Mental Health (NIMH) and National Institute of Child
Health and Human Development.
The gene, GAD1, makes an enzyme essential for production of the
chemical messenger, called GABA. The more the gene is turned on,
the more GABA synthesis can occur, under normal circumstances.
GABA helps regulate the flow of electrical traffic that enables
brain cells to communicate with each other. It is among the major
neurotransmitters in the brain.
Abnormalities in brain development and in GABA synthesis are known
to play a role in schizophrenia, but the underlying molecular mechanisms
are unknown. In this study, scientists discovered that defects
in specific epigenetic actions — biochemical reactions that
regulate gene activity, such as turning genes on and off so that
they can make substances like the GAD1 enzyme — are involved.
Results of the research were published in the October 17 issue
of the Journal of Neuroscience, by Schahram Akbarian,
MD, PhD, Hsien-Sung Huang, PhD student, and colleagues at the University
of Massachusetts Medical School and Baylor College of Medicine.
"This discovery opens a new area for exploration of schizophrenia," said
NIMH Director Thomas R. Insel, MD. "Studies have yielded
very strong evidence that schizophrenia involves a decrease in
the enzymes, like GAD1, that help make the neurotransmitter GABA.
Now we're starting to identify the mechanisms involved, and our
discoveries are pointing to potential new targets for medications."
Another enzyme, Mll1, may play a role in the epigenetic actions.
For genes to be turned on, temporary structural changes in certain
proteins — histones — must take place to expose the
genes' blueprints in DNA. The researchers found evidence that,
in schizophrenia, changes in Mll1 activity may interfere with this
process in histones whose alterations enable the GAD1 blueprint
to be exposed.
The researchers also showed, in mice, that antipsychotic medications
like clozapine appear to correct this epigenetic flaw. This raises
the possibility of developing new medications aimed at correcting
defects in the mechanisms involved.
Finding more precise molecular targets for development of new
schizophrenia medications is a key effort, because it can lead
to more effective treatments with fewer side effects. Clozapine
and other current antipsychotic medications are effective for many
patients, but not all, and they can cause side effects severe enough
that some people choose to stop treatment.
The researchers also found that people with three different variations
of the GAD1 gene — variations previously associated with
schizophrenia — also were more likely to have indicators
of a malfunction in brain development. Among them were indicators
of altered epigenetic actions related to GABA synthesis.
"We've known that schizophrenia is a developmental disease,
and that something happens in the maturation of the prefrontal
cortex during this vulnerable period of life. Now we're beginning
to find out what it is, and that sets the stage for better ways
of preventing and treating it," Akbarian said.
For more information, visit the NIMH web site at http://www.nimh.nih.gov/health/topics/schizophrenia/index.shtml
The National Institute of Mental Health (NIMH) mission is to reduce
the burden of mental and behavioral disorders through research
on mind, brain, and behavior. More information is available at
the NIMH website: http://www.nimh.nih.gov/.
The National Institutes of Health (NIH) — The Nation's
Medical Research Agency — includes 27 Institutes and
Centers and is a component of the U.S. Department of Health and
Human Services. It is the primary federal agency for conducting
and supporting basic, clinical and translational medical research,
and it investigates the causes, treatments, and cures for both
common and rare diseases. For more information about NIH and
its programs, visit www.nih.gov.