Common gene version optimizes thinking -- but with a possible downside

Feb 08, 2007

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 Meyer-Lindenberg, M.D.

"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.

Source: NIH/National Institute of Mental Health

Explore further: Education, breastfeeding and gender affect the microbes on our bodies

add to favorites email to friend print save as pdf

Related Stories

Research team implants human innate immune cells in mice

Mar 18, 2014

(Phys.org) —Overcoming a major limitation to the study of the origins and progress of human disease, Yale researchers report that they have transplanted human innate immune cells into mouse models, which ...

Multiple sensory cues draw mosquitoes to hosts

Feb 28, 2014

It may seem like mosquitoes will bite anything with a pulse, but they're actually quite strategic in picking their victims. A new study from The Rockefeller University looked at the interaction of different ...

Recommended for you

Leeches help save woman's ear after pit bull mauling

15 hours ago

(HealthDay)—A pit bull attack in July 2013 left a 19-year-old woman with her left ear ripped from her head, leaving an open wound. After preserving the ear, the surgical team started with a reconnection ...

New pain relief targets discovered

Apr 17, 2014

Scientists have identified new pain relief targets that could be used to provide relief from chemotherapy-induced pain. BBSRC-funded researchers at King's College London made the discovery when researching ...

User comments : 0

More news stories

Treating depression in Parkinson's patients

A group of scientists from the University of Kentucky College of Medicine and the Sanders-Brown Center on Aging has found interesting new information in a study on depression and neuropsychological function in Parkinson's ...