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Genetically Altered Mice Give Researchers Insight in Study of Schizophrenia

Posted on: Tuesday, 1 July 2003, 06:00 CDT

Jul. 1--A genetically engineered mouse that behaves much like a human schizophrenic may have yielded one of the best clues yet to the inherited causes of schizophrenia, according to new research by scientists at the Massachusetts Institute of Technology and elsewhere.

The mouse study, released yesterday, pinpointed a gene that can offer "a totally new molecular target for antischizophrenia drug development," said Susumu Tonegawa, a Nobel laureate at MIT who led the study.

Schizophrenia is one of the most common and devastating of psychiatric diseases, afflicting almost 5 million Americans and an estimated 1 percent of the global population. Patients may experience hallucinations, confusion, emotional flatness and other symptoms. Although current drugs can help, they often fail or have major side effects.

Other researchers recently have reported finding genes linked to schizophrenia, but this latest study provided unusually strong evidence. Tonegawa found that when the gene was eliminated in mice, they showed several behaviors resembling schizophrenia, including social withdrawal and memory problems. A follow-up study in humans found schizophrenics were more likely to carry a variant of the gene.

"This combination of mouse genetics and human genetics makes the best case I know of for a gene associated with schizophrenia," said Stephen Heinemann, a professor at the Salk Institute for Biological Studies in La Jolla, Calif., who was not involved in the study.

Research into the genetics of schizophrenia has long frustrated scientists. It is a complex disease with complex genetics, and good animal models have been hard to come by.

But there have been notable signs of progress lately, along with new impetus for research.

A new group called the Consortium on the Genetics of Schizophrenia has launched a project financed for five years by $20 million from the National Institute of Mental Health. Its seven academic centers, which include Harvard, will try to tease apart the connection between various aspects of schizophrenia and genes.

Already, scans of individual schizophrenics' genomes have helped researchers identify eight to 10 major genes that influence the disease, said David Braf, director of the consortium and head of schizophrenia research at the University of California at San Diego.

"Now we're beginning to understand what those [genes] do," he said.

The Tonegawa study, published in the Proceedings of the National Academy of Sciences, focused on an enzyme called calcineurin, a common signaling molecule in both the body and the brain.

His group, which studies memory, initially produced the mouse with the calcineurin gene knocked out in the front part of their brains, resulting in mice with impaired short-term memories.

Then a postdoctoral fellow, Tsuyoshi Miyakawa, examined the behavior of the mice more closely and found that along with their memory problems, they were unusual in several ways that parallel behavior of human schizophrenics, said Tonegawa, director of the Picower Center for Learning and Memory at MIT. Normal mice cuddle together when they share a cage, but the mutant mice chose to sleep alone, he said. Normal mice build nests from shredded paper in the cage, but the mutants kept their cages disorganized. The mutants were also more easily startled, a sign of attention problems that is used to diagnose humans, as well.

Colleagues at the Rockefeller Institute and elsewhere bolstered the mouse findings with gene scans from 410 families with a tendency toward schizophrenia. They concluded that a gene connected to calcineurin may be contributing to susceptibility to schizophrenia, researcher Maria Karayiorgou said.

"I would say that it's an important finding," she added. But "there's still a lot of work that needs to be done before this can be translated" into help for patients.

However, the mouse model also means that researchers can initially test potential drugs in animals rather than humans, a much more appetizing prospect for companies. And the identification of calcineurin as a good target, Tonegawa said, could mean that a drug could be developed more rationally than by "trial and error."

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(c) 2003, The Boston Globe. Distributed by Knight Ridder/Tribune Business News.

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