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Schizophrenia and Schizotypal Personality may have Genetic Roots 

NIH Researchers Report That Knockout Of Mouse Gene Results In Unexpected Social and Behavioral Changes

Bethesda, MD- Scientists at the National Institutes of Health (NIH) report in the September 5, 1997 issue of Cell that they have identified a gene that disrupts normal social behavior among laboratory mice missing that gene.

In addition, these mutant mice have abnormalities in sensorimotor gating - a process believed to be important in animals for filtering the multitude of stimuli that constantly bombard their senses and allowing them to focus on one stimulus at a time.

Sensorimotor gating defects are also believed to contribute to symptoms of several human neuropsychiatric disorders, including schizophrenia, schizotypal personality disorder, obsessive-compulsive disorder, Huntington's disease and Tourette syndrome. All of these human disorders appear to have genetic components, but the specific gene disrupted in these mice, dishevelled-1, has not previously been associated with any of them.

The researchers say their data suggest that the gene and others related to it are candidate genes for several human neuropsychiatric disorders. They expect the mouse mutants to prove useful in studying aspects of these human neuropsychiatric disorders, and possibly in testing new drug treatments.

The researchers were surprised when mice missing dishevelled-1 turned out to have behavioral defects. "We wouldn't have predicted the mice would have social interaction abnormalities or other behavioral abnormalities," says senior author Anthony Wynshaw-Boris, who heads a laboratory in the NHGRI Laboratory of Genetic Disease Research.

The mutant mice were created by inactivating the dishevelled-1 gene in mouse embryos. The "knock-out" mice produce no dishevelled-1 protein, but appear to develop just like control mice. Control mice are genetically identical to the mutant mice except for their normal dishevelled-1 genes.

The researchers decided to study the mouse gene because it is structurally similar to others in a family of genes found throughout the animal kingdom and thought to play a basic role in early development. The gene was first identified in the fruit fly Drosophila and was named dishevelled (dsh) because, when mutated, it creates a disorganized fruit fly larva that cannot survive.

Drosophila possess only one dishevelled gene. Three dishevelled genes have been identified so far in both mice and humans. The three mouse genes were first by Daniel J. Sussman at the University of Maryland School of Medicine in Baltimore, a collaborator on the Cell paper. No known biochemical function has been associated yet with any of the proteins made by dishevelled genes. The mammalian versions probably have overlapping functions, however, because the dishevelled-1 mutation does not interfere with mouse development in any obvious way.

The dishevelled-1 mutant mice are healthy and fertile, with a normal life span and what appear to be structurally normal brains and learning ability reports the paper, whose co-first authors are Nardos Lijam of the Laboratory of Genetic Disease Research at NHGRI and Richard Paylor of the Section on Behavioral Neuropharmacology at the National Institute of Mental Health (NIMH). But the mutants interact with other mice less than non mutants do.

One visible consequence is that, when housed together, the mutant mice retain their whiskers and facial hair, which in most of the control mice are usually trimmed away by the dominant mouse in the group. The mutant mice are less likely to display other dominance behaviors. Their sleeping arrangements are also peculiar. The mutants tend to sleep in atypical scattered, random patterns rather than huddled together like most mice. They are also inept at building nests for sleeping, a characteristic mouse behavior.

In the paper, the scientists conclude that the results of their studies with the mice "are consistent with an interpretation that common genetic mechanisms underlie abnormal social behavior and sensorimotor gating defects, and implicate dishevelled-1 in processes underlying complex behaviors." They plan to explore whether the behavioral effects of dishevelled-1 mutations in mice extend to other social behavior, such as aggression.

"There are different ways that dishevelled-1 might affect complex behavior," says Dr. Wynshaw-Boris. "During fetal development, it may play a role in the formation of subtle structures in the central nervous system that are critical for the behavior. Alternately, after birth, it may act in the brain, perhaps by affecting the transmission of nerve impulses. One section of the normal dishevelled-1 protein is structurally similar to parts of other proteins known to link proteins at the synapses between nerve cells, where nerve impulses are passed from cell to cell."

At NIMH, Dr. Paylor worked in the laboratory of Jacqueline Crawley. Other authors on the paper include Michael McDonald of NIMH, Chu-Xia Deng of the National Institute of Diabetes, Digestive and Kidney Diseases, Gianmaria Maccaferri and Chris McBain of the National Institute of Child Health and Development, all of the National Institutes of Health; Karl Herrup of Case Western Reserve University School of Medicine; and Karen Stevens of the University of Colorado Health Science Center.

NHGRI oversees the NIH's role in the Human Genome Project, an international research effort to develop tools for gene discovery.

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