CHAPEL HILL, N.C. - The first potential genetically engineered animal model for schizophrenia -- a long-term, disabling mental illness afflicting 1.5 million U.S. residents -- has been created by University of North Carolina at Chapel Hill scientists collaborating with Duke University researchers.
Their achievement promises to boost research into the heartbreaking illness and eventually improve drug therapy and other treatments, the scientists say.
"You can't diagnose mental illness in mice, and so we can't say definitely that these mice actually have schizophrenia," said Dr. Amy R. Mohn, who earned a genetics doctorate at UNC-CH and became a postdoctoral fellow at Duke in January. "We can say, however, that they display behaviors consistent with schizophrenia and should be very useful in studying it."
A report on the research appears in the Aug. 20 issue of the journal Cell. Besides Mohn, a UNC-CH Curriculum in Genetics and Molecular Biology graduate, authors are Drs. Beverly H. Koller, research assistant professor of medicine at the UNC-CH School of Medicine; Marc G. Caron, James B. Duke professor of cell biology at Duke; and Caron's postdoctoral fellow Raul R. Gainetdinov, a visiting Russian scientist.
"What's interesting about this mouse is that we have targeted a neurotransmitter receptor that has been implicated in the disease but has not been the chief focus of schizophrenia research," Mohn said. "Most recent previous research has looked at a transmitter called dopamine, but our paper describes the importance of what's called the NMDA receptor."
NMDA receptors are a subgroup of glutamate receptors known to play critical roles in nerve development and physiology, she said. Neurotransmitters are small molecules that signal nerve cells to fire.
The new genetically engineered mice survive to adulthood and behave abnormally by repeating various activities such as grooming and interact poorly with other mice in social and sexual situations,the scientist said. Affected females often don't produce offspring but neglect their young when they do give birth.
Currently used mouse models for schizophrenia are created by giving the rodents compounds such as PCP.
"These mice are the first to display schizophrenia-like behaviors without being treated with PCP or comparable chemicals to cause those behaviors," Mohn said. "We created it in part to test the idea that schizophrenia may actually result from decreased function of NMDA receptors even though drugs currently used act on the dopamine system. The surprising thing is that we can generate these mice that have symptoms like schizophrenia by targeting a different neurotransmitter system."
Mohn and Koller created the mice in Chapel Hill by altering genes in mouse embryonic stem cells, implanting the cells in new embryos and then transferring the embryos into foster mothers where they developed. They then bred successive generations of the mice and showed that about 25 percent carried the mutation and displayed schizophrenia-like behaviors.
Several years ago, Koller used the method, pioneered by Dr. Oliver Smithies, to create the first animal model for cystic fibrosis. Smithies is Excellence professor of pathology and laboratory medicine at UNC-CH.
"We believe this new work will be useful for two reasons," Mohn said. "First, it will cause researchers to look at NMDA receptors as a therapeutic target for schizophrenia. Second, it will help in testing new drugs. That should be much better than the current system of giving drugs to create the psychosis symptoms and then other drugs to counteract them and normalize behaviors."
Schizophrenia, which is incurable, often shows up in late adolescence and disrupts young lives to varying degrees, often radically. Symptoms can include moderate to severe paranoia, hallucinations, delusions, otherwise impaired thinking and withdrawal from people.
Compared with earlier times -- when patients could be institutionalized for life -- treatments have improved markedly, especially in recent decades, she said. Still, drug therapy fails in some people and can carry undesirable side effects that cause patients to stop taking their medicines.
The National Institutes of Health and the Howard Hughes Medical Institute supported the research.
Note: Mohn can be reached at (919) 681-4549 (w) or 419-6107 (h). Contact: David Williamson, 962-8596.
Journal
Cell