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School of Medicine
News from the Department of Psychiatry and Behavioral Science
|Dr. Akira Sawa|
For almost a decade, the idea’s been out that schizophrenia starts before birth. Structure points to it: Patients’ brains have abnormally large ventricles early in the disease, for example—too early to be a side effect of prescribed drugs. And the ranks of orderly layers of cells that define the cerebral cortex, laid down in development, have gone higgledy-piggledy. Missing, too, are the tell-tale signs of gradual neurodegenerative diseases like Parkinson’s or Alzheimer’s. But, so far, nothing direct has shown the disease begins in utero.
So the report from Akira Sawa’s laboratory this past fall that a gene tied to a rare form of schizophrenia also warps early brain development—and Sawa has good ideas how—is real news. And that brains of animal models carrying the gene resemble nothing so much as humans with schizophrenia makes the find especially compelling.
The work may well be a toehold sort of discovery, like learning beta amyloid is a culprit in Alzheimer’s disease—a real boost for research to come. “It’s already suggested new paths for therapy that we’re exploring intensely,” says Sawa.
Sawa had followed the work of Scottish scientists who’d come across a family with major mental illness, a large group plagued by apparently “pure” schizophrenia, mood disorders and blends thereof. The cause had to be something genetic. With a pedigree in hand, the Scots traced the illness to a mutant gene they called Disrupted in Schizophenia—DISC1 for short. Interestingly, others have suggested loose ties between DISC1 and more common forms of schizophrenia.
Sawa’s group picked up the DISC1 work, not studying the disease in patients, but starting with the flawed gene—an approach rare in psychiatric research. Because they suspected that DISC1’s protein product somehow interferes with brain development, they focused on cell machinery that, early on, eases embryonic neurons outward to proper brain targets. A series of elegant experiments in mouse models revealed that mutant DISC1 graphically uncouples that machinery—the microtubule “girders” and the motor that moves them—from its anchoring point in the cell.
The result, cultures show, is the cell equivalent of shyness; neurons don’t branch out. And in live mouse models, the layering of the cerebral cortex (right) looks abnormal. “It’s very similar to what we see in human schizophrenia,” Sawa says, “but that needs verifying.” Other team studies show that the sine qua non—animal behavior—is off too, leaving Sawa enthusiastic about the possibility that his DISC1 animal model of schizophrenia is the first good one.
A model could speed work on two fronts: Sawa has signs (right) that the brain compensates somewhat for developmental upsets. Could that be enhanced? He also hopes for “a conceptual breakthrough” to shed light on the commonest forms of schizophrenia—one that shows something environmental, like a virus, feeds into DISC1’s pathway in the brain. Both ideas have his team living in the lab.
For information about Dr. Sawa's research, call: 410-955-4726.