White Matter Defects May Lead to Schizophrenia

Study suggests a genetic connection that could lead to new therapies

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HealthDay Reporter

TUESDAY, April 24, 2007 (HealthDay News) -- Defects in the brain's white matter, which is responsible for communication between parts of the brain, may be a key genetic factor contributing to schizophrenia, a new study suggests.

"This is the first clear demonstration of a new mechanism by which aspects of schizophrenia and other disorders could be produced," said study senior author Gabriel Corfas, an associate professor of neurology and otolaryngology at Harvard Medical School.

"On the one hand, this may help us to understand and start thinking about novel treatment strategies," added Corfas, a member of the neurobiology program at Children's Hospital Boston. "Secondly, this may help in early detection and, nowadays, we know that this is critical."

The study also illuminates how two genes previously linked to schizophrenia actually contribute to the disease, the researchers said.

Schizophrenia is a devastating disease that affects some 1 percent of the world's population. According to the U.S. National Institute of Mental Health, people with the disease sometimes hear voices that aren't there, believe that others are broadcasting their thoughts to the world, or become convinced that others are trying to harm them. These fears can make patients withdrawn and cause difficulties when they try to have relationships with others.

The causes of schizophrenia aren't clear but, in the last decade, there's been a growing awareness that patients with this and other neuropsychiatric disorders may have defects in the white matter of the brain.

"Until now, it was not clear whether the white matter defects are a cause of the disease or a result of being treated with drugs and being sick," Corfas explained.

Also, prior studies had linked schizophrenia to the genes for neuregulin 1 (NRG1), a growth factor involved in brain development, along with erbB4, a receptor on brain cells through which NRG1 works.

"It was found that if people have particular variants, the likelihood that they will have neuropsychiatric disease is enhanced," Corfas said. "We had hypothesized for many years that these genes were important for formation of white matter, so that brought together the possibility that maybe these genes, when they are defective, generate white matter that is defective and that causes aspects of neuropsychiatric disorder."

"What we wanted to determine was whether altering white matter can affect aspects of the disease," he continued.

Corfas and his team blocked NRG1-erbB signaling in oligodendrocytes in mice. Oligodendrocytes are the cells that form the myelin, or fatty encasing, of nerve fibers. The brain's white matter is made up of myelinated nerve fibers.

When the signaling was blocked, the mice had more oligodendrocytes than normal mice, but the cells had fewer branches and formed a thinner sheath around the nerve fibers. This resulted in slower conduction of electric impulses.

The mice also had alterations in the nerve cells that make and use dopamine, a brain chemical that is known to be altered in people with schizophrenia.

The behavior of the mice was also altered.

"Alterations in signals cause defects, very specific and relatively subtle in white matter structure and function, and these cause dramatic effects on behavior that are in some ways similar to what you would expect to see in neuropsychiatric patients," Corfas said. "They also involve alterations in neurochemicals that are known to be altered in schizophrenia."

The findings are expected to be published online by the Proceedings of the National Academy of Sciences during the week of April 23.

Keith A. Young is associate professor of psychiatry and behavioral science at Texas A&M Health Science Center College of Medicine and co-director of the Central Texas Veterans Health Care System Neuropsychiatry Research Program, who recently presented a paper on this topic at the International Congress on Schizophrenia Research. He said: "What they (the study authors) did in this study was only manipulate this gene or this gene product in white matter, so it's pretty clear that the genetic defects that we've seen in schizophrenia may be being expressed through the white matter and not other cell types. They were so specific in genetic manipulation that it really tightly links this receptor with myelin deterioration."

But Young also cautioned that animal models of schizophrenia are far from perfect.

"In reality, there are no good animal models of schizophrenia," he said. "It's just hard to make a rat act like they're psychotic. It's just such a human behavior. We don't know if they're delusional. We don't know if they're hallucinating."

Still, the new findings are intriguing and could also have implications for bipolar disorder, which also seems to involve NRG1 and white matter defects.

"This may help identify people who are at risk," Corfas said. "The current idea about schizophrenia is that it's a developmental disorder, that when we grow up, something in the way our brains are developed puts us at risk. Something could make us lose the balance. It could be drugs. It could be emotional stress. It could be anything, so identifying people who are at risk might help develop the tools and strategies to protect them."

More information

Visit the U.S. National Institute of Mental Health for more on schizophrenia.

SOURCES: Gabriel Corfas, Ph.D., associate professor of neurology and otolaryngology, Harvard Medical School, and member of the neurobiology program, Children's Hospital Boston; Keith A. Young, Ph.D., associate professor of psychiatry and behavioral science, Texas A&M Health Science Center College of Medicine, and co-director of the Central Texas Veterans Health Care System Neuropsychiatry Research Program; April 23-27, 2007, Proceedings of the National Academcy of Sciences

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