Of all the human pathologies that scientists have attempted to model in animals, perhaps none is as difficult as schizophrenia. Striking about 1 percent of the population, the disease is marked by three broad types of symptoms: positive (delusions, hallucinations), negative (withdrawal, lack of expression), and cognitive (poor working memory, short attention span).

It’s a formidable recipe. Against these considerable odds, however, two HHMI investigators have had success in approximating certain aspects of the disease in animal models.

Over the years several studies have reported that antipsychotic drugs ameliorate schizophrenia by blocking excessive dopamine transmission in the brain. In 2004, researchers learned that these patients often have large numbers of D2 dopamine receptors in the striatum, an area deep within the brain that controls movement and balance. In an attempt to extend this finding, Eric R. Kandel’s Columbia University lab created mice that also overexpressed these receptors, and his team discovered that the mice suffered a hallmark of schizophrenia: impaired working memory. This deficit persisted even when the researchers allowed production of D2 receptors to return to normal.

Early in an animal’s development, Kandel reasoned, the damage caused by increased dopamine transmission may produce irreversible changes in other parts of the brain.

But dopamine may not be the only culprit. Calcineurin is an enzyme involved in the regulation of the immune response and in learning. In 2001, HHMI investigator Susumu Tonegawa and his colleagues at the Massachusetts Institute of Technology found that knock-out mice missing calcineurin in the forebrain also suffer impaired working memory. And the mutants display other symptoms reminiscent of schizophrenia: They are hyperactive and withdrawn from other animals, for example, and they are more easily startled than normal mice.

“Based on our mouse study, we were able to go on to obtain direct genetic evidence that variation in a human calcineurin gene is associated with schizophrenia susceptibility in humans,” says Tonegawa. “These data provide strong support for the involvement of calcineurin-related genes in schizophrenia etiology.”

Precisely which of these are involved is still a mystery, and in any event the disease is likely to depend on interaction with the environment. Adds Tonegawa, “In recent years, real progress has been made in identifying disease genes. We hope that advances like our calcineurin findings will ultimately lead to better therapies.”

—M.M.

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