|Brain Scans Reveal How Gene May Boost Schizophrenia
Clues about how a suspect version of a gene may slightly increase
risk for schizophrenia* are emerging from
a brain imaging study by the National Institutes of Health’s
(NIH) National Institute of Mental Health (NIMH). The gene variant
produced a telltale pattern of activity linked to production of
a key brain messenger chemical.
The study found that increased activity in the front of the brain
predicted increases in the neurotransmitter dopamine in the middle
of the brain in subjects with the suspected schizophrenia-related
version of the gene. Yet, the opposite relationship held for subjects
with the other of two common versions of the gene.
“A tiny variation in the gene that makes the enzyme that
breaks down dopamine causes a complete flipflop not a mere
difference in degree in dopamine activity in these two brain
areas,” explained NIMH’s Dr. Andreas Meyer-Lindenberg,
who, along with Dr. Karen Berman and colleagues, reported their
findings in the April 10, 2005 online edition of Nature Neuroscience.
The NIMH study also for the first time confirms in living humans
that activity of the front brain area, the prefrontal cortex, is
regulated by dopamine production in the midbrain, which, in turn,
is regulated by these two common gene variants.
Schizophrenia, a severe mental illness marked by hallucinations
and delusions, affects one percent of the population and is treated
with antipsychotic drugs that block dopamine. The prefrontal cortex
is critical for motivation, learning in response to reward, and
working memory functions impaired in schizophrenia, which
is thought to involve a dopamine imbalance.
Individuals inherit two copies (one from each parent) of the gene
for the enzyme catecho-O-methyltransferase (COMT), which chemically
breaks down dopamine. It comes in two versions, val and met,
so a person can have two of the same version or one of each. Since
it results in considerably weaker enzyme action, people with the met version
are thought have more dopamine in their prefrontal cortex and perform
better on tasks involving that part of the brain. Schizophrenia
patients typically perform poorly on such tasks. Earlier studies
had shown that inheriting two copies of the more common val version
leads to a slightly higher risk for schizophrenia and a signature
pattern of midbrain dopamine activity.**
To see how the two gene versions affect the living human brain,
the NIMH researchers scanned 24 healthy young adults twice using
PET (positron emission tomography), which uses radioactive tracers
to visualize brain function. The first scan measured subjects’ overall
brain activity while they performed working memory tasks. The second
scan used a dopamine tracer to reveal the synthesis of the neurotransmitter
in the midbrain.
Frontal cortex activity increased as midbrain dopamine activity
increased in subjects with val, but decreased in those who
had inherited two copies of the met COMT gene.
This “trait-like characteristic” of COMT gene type
fits a model in which the prefrontal cortex functions optimally
when dopamine activity is neither too low nor too high, corresponding
to the top of an upside-down “U” (see diagram below).
In this model, people with val fall on the left (rising)
slope, with lower dopamine levels, while those with met fall
on the right (falling) slope, with higher dopamine levels.
The findings suggest that dopamine “tunes” prefrontal
neurons (brain cells) to achieve an optimal signal-to-noise ratio,
much like a fine-tuning dial on a radio. For the clearest signal,
the “dial” must be turned in opposite directions, depending
on which version of the COMT gene one inherits: up with val,
down with met. In people with val and schizophrenia,
which is marked by too little prefrontal and too much midbrain
dopamine, the dial is turned “way up,” the NIMH researchers
“ We expected that there would be different regulatory mechanisms
between the two gene types, but it’s amazing how well the
data support this tuning model,” said Berman. “The
study is important for our understanding of schizophrenia because
it clarifies the neural mechanism for a well-established risk gene.”
Also participating in the NIMH brain imaging study were: Dr. Daniel
Weinberger, Philip Kohn, Dr. Bhaskar Kolachana, Shane Kippenhan,
NIMH; Dr. Aideen McInerney-Leo, Dr. Robert Nussbaum, National Human
Genome Research Institute (NHGRI).
|An inverted “U” models
the relationship between COMT gene type, prefrontal cortex
activity, and prefrontal dopamine levels. The cortex functions
optimally when dopamine activity is neither too low nor
too high, corresponding to the top of the curve. Dopamine
is thought to “tune” prefrontal neurons by
regulating signal-to-noise ratios – but in opposite
directions, depending on whether an individual has inherited
the val or met COMT gene type.
Source: NIMH Clinical
Brain Disorders Branch
|Areas in prefrontal
cortex where blood flow (yellow) was linked to midbrain
dopamine synthesis, in opposite directions in subjects
with val and met COMT gene type. PET data is superimposed
on 3-D MRI view of brain.
Source: NIMH Clinical Brain Disorders
NIMH and NHGRI are part of the National Institutes of Health
(NIH), the Federal Government's primary agency for biomedical
and behavioral research. NIH is a component of the U.S. Department
of Health and Human Services.