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Patients' own cells yield new insights into the biology of schizophrenia

Nature

Fred "Rusty" Gage and Kristen Brennand in the lab


Even after a century of studying the causes of schizophrenia—the most persistent disabling condition among adults—scientists still don't know the cause of the disorder. Induced pluripotent stem cells (iPSCs) generated from schizophrenic patients, however, have brought researchers from the lab of Fred H. Gage a step closer to a fundamental understanding of the biological underpinnings of the disease.

In their study, published in Nature, Gage's team reported both that neurons generated from these patient-derived iPSCs made fewer connections with each other and that Loxapine, an antipsychotic drug commonly used to treat schizophrenia, restored neuronal connectivity in iPSC neurons from all patients.

"This is the first time that a complex mental disease has been modeled in live human cells," says Gage. "This model not only affords us the opportunity to look at live neurons from schizophrenia patients and healthy individuals to understand more about the disease mechanism, but also to screen for drugs that may be effective in reversing it."

Schizophrenia, which is defined by a combination of paranoid delusions, auditory hallucinations and diminished cognitive function, afflicts 1 percent of the population worldwide, corresponding to nearly 3 million people in the United States alone. Accumulating genomic evidence indicates that many different combinations of genetic lesions—some of them affecting the susceptibility to environmental influences—may lead to a variety of signs and symptoms collectively labeled schizophrenia.

Trying to overcome the limitations of the past, such as limited accessibility of human neurons and the difficulty of separating genetic and environmental influences, postdoctoral researcher Kristen Brennand reprogrammed into iPSCs skin fibroblasts from four schizophrenia patients with a hereditary history of the disease. She then differentiated these cells into neurons, which allowed her to study how they differed from those in non-schizophrenics.

"Nobody knows how much the environment contributes to the disease," she explains. "By growing neurons in a dish, we can take the environment out of the equation and start focusing on the underlying biological problems."

"For many years, mental illness has been thought of as a social or environmental disease, and many thought that if affected people just worked through their problems, they could overcome them," adds Gage. "What we are showing are real biological dysfunctions in neurons that are independent of the environment."