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Schizophrenic Mice

More than two million people in the United States have schizophrenia, yet the disorder remains a medical mystery. Scientists don't know precisely what causes some brains to produce hallucinations, delusions and disordered thinking. One reason it's particularly hard to study schizophrenia is that it doesn't seem to occur in animals. But as NPR's Jon Hamilton reports, a small group of scientists at the National Institutes of Health are using genetic engineering to reproduce some of the symptoms of schizophrenia -- in mice.

At the National Institute of Mental Health in Bethesda, Md., one laboratory, run by Dr. Jacqueline Crawley, is home to hundreds of mice that have been genetically altered to mimic the symptoms of people with all kinds of mental problems. Some act anxious -- they won't explore exposed areas. Others show a symptom associated with depression -- they give up quickly when placed in stressful situations.

But perhaps the most intriguing mouse models are those used to study schizophrenia. Dr. Thomas Insel, director of the National Institute of Mental Health (NIMH), explains why.

"When you look at the use of a mouse to model human disorders, there are some places where it's fairly straightforward," Insel explains. "I don't think most people have a problem understanding that mice can have seizures that look like human seizures. But the question comes up over and over again -- do mice develop schizophrenia? What would a hallucinating mouse look like? And the answer to that question is that no one really knows."

Crawley's team of researchers doesn't expect to solve that mystery. Her lab's goal is to identify strains of mice whose behavior in some ways merely approximates symptoms seen in people with schizophrenia. The researchers have already had success reproducing in mice one symptom of the disorder -- a tendency to startle.

When a normal brain knows a loud sound is coming, it reacts less strongly than if the sound is a total surprise. That diminished response, known as prepulse inhibition, is much less pronounced in schizophrenics.

To identify mice with this same behavioral disorder, Crawley places them in a special chamber, where they are subjected to loud tones. Some of the noises are sudden. Others are preceded by a barely audible warning just a split second before the loud noise. Sensors measure the amplitude of each mouse flinch in response to the noises. Crawley says the results are clear: Several genetically modified mice flinch even after the warning sound -- just the way someone with schizophrenia would.

But the feat of genetic engineering will be useful only if scientists prove that tweaking the mouse genes has affected the same brain circuits that are disrupted in schizophrenia. Evidence so far is encouraging. Drugs that help people with schizophrenia also help the flinching mice.

Insel says that might mean the mouse model could be used to test new drugs. And he says eventually it could lead to entirely new ways of treating schizophrenia and other disorders that damage the brain over many years.

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Jon Hamilton is a correspondent for NPR's Science Desk. Currently he focuses on neuroscience and health risks.