|Common Gene Version Optimizes Thinking — but
With a Possible Downside
Most people inherit a version of a gene that optimizes their brain’s
thinking circuitry, yet also appears to increase risk for schizophrenia*,
a severe mental illness marked by impaired thinking, scientists
at the National Institutes of Health’s (NIH) National Institute
of Mental Health (NIMH) have discovered. The seeming paradox emerged
from the first study to explore the effects of variation in the
human gene for a brain master switch, DARPP-32.
The researchers identified a common version of the gene and showed
how it impacts the way two key brain regions exchange information,
affecting a range of functions from general intelligence to attention.
Three fourths of subjects studied had at least one copy of the
version that results in more efficient filtering of information
processed by the brain’s executive hub, the prefrontal cortex.
However, the same version was also more prevalent among people
who developed schizophrenia, a severe mental illness marked by
delusions, hallucinations and impaired emotion that affects one
percent of the population.
“We have found that DARPP-32 shapes and controls a circuit coursing
between the human striatum and prefrontal cortex that affects key
brain functions implicated in schizophrenia, such as motivation,
working memory and reward related learning,” explained Andreas
“Our results raise the question of whether a gene variant favored
by evolution, that would normally confer advantage, may translate
into a disadvantage if the prefrontal cortex is impaired, as in
schizophrenia,” added Daniel Weinberger, M.D. “Normally, enhanced
cortex connectivity with the striatum would provide increased flexibility,
working memory capacity and executive control. But if other genes
and environmental events conspire to render the cortex incapable
of handling such information, it could backfire — resulting
in the neural equivalent of a superhighway to a dead-end.”
Meyer-Lindenberg, Weinberger and colleagues in the NIMH Genes,
Cognition and Psychosis program report their results in the February
9, 2007 issue of the Journal of Clinical Investigation.
Previous studies in animals over two decades, most notably by
Nobel Laureate and NIMH grantee Paul Greengard, M.D., Rockefeller
University, had established that DARPP-32 in the striatum switches
streams of information from multiple brain chemical systems for
processing by the cortex. Both the neurotransmitter that it works
through, dopamine, and the chromosomal site of its gene have been
implicated in schizophrenia.
“Although several groups have looked for possible clinical relevance
of DARPP-32, they have not met with great success,” noted Greengard. “This
study shows a strong connection between this molecule and human
cognition — and perhaps with schizophrenia.”
“These first glimpses of DARPP-32 at work in the living human
brain build on a quarter century of investigations by Greengard’s
team that ultimately linked this pivotal protein to depression
and substance abuse as well as to schizophrenia,” added NIMH Director
Thomas Insel, M.D.
To understand DARPP-32’s role in the human brain, the NIMH researchers
used genetic, structural and functional magnetic resonance imaging,
and post-mortem techniques to identify the human gene's variants
and their functional consequences. Seventy five percent of subjects
had the most common version of the gene, which boosted circuit
activation, structural and functional connectivity and performance
on thinking tasks, likely by increasing gene expression. In 257
affected families, people with schizophrenia were more likely to
have this common version of the DARPP-32 gene.
Also participating in the study were: Richard Straub, Barbara
Lipska, Beth Verschinski, Terry Goldberg, Joseph Callicott, Michael
Egan, Stephen Huffaker, Venkata Mattay, Bhaskar Kolachana, Joel
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
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.