An Up-Close View of Schizophrenia

Reprogrammed cells generated from people with schizophrenia could help scientists study the disease more closely, according to a study published online today in Nature. Such cells would allow scientists to look at the disease on a cellular level, and also test potential drugs to combat the condition.

Researchers from the Salk Institute for Biological Studies began with skin cells taken from schizophrenic patients, which they reprogrammed to create induced pluripotent stem (iPS) cells—adult cells that have been transformed chemically or genetically into stem cells capable of giving rise to any type of tissue. They then coaxed those cells to differentiate into neurons. Scientists found that the diseased neurons made fewer connections with one another than did healthy neurons—a problem that antischizophrenia medication could alleviate.

The study is one of several recent papers showing that iPS cells derived from patients with specific diseases could give new insight into those complex diseases. Previous studies on iPS-derived neurons have focused on diseases with specific genetic mutations, and those that develop in early childhood.

Schizophrenia, however, is a more complex disease. It has both genetic and environmental origins, and often develops in adolescence or early adulthood. “This paper opens up the possibility that even psychiatric diseases can be potentially investigated using these cell models,” says Kwang-Soo Kim, a stem-cell scientist at McLean Hospital and Harvard Medical School who was not involved in the study.

Fred Gage, a neuroscientist who led the Salk Institute study, says that much of what is known about differences in the brains of schizophrenia patients comes from examining brain tissue after death. Scientists can also use animal models engineered to mimic some of the genetic changes linked to the disease to study the impact of these mutations, but such models don’t capture the full complexity of schizophrenia.

But with neurons created from reprogrammed skin cells, Gage says, “the advantage is you’re looking for the first time at living neurons from patients who have the disease.”  

The researchers used skin cells taken from four patients with schizophrenia to create iPS cells, which they then differentiated into neurons. They compared these cells to neurons derived from people without the disease.

After infecting cells with a modified rabies virus and then watching the spread of the virus from cell to cell, the researchers found that cells from people with schizophrenia formed fewer connections with one another, and made fewer projections to reach out to other cells. The researchers also performed an analysis of gene activity in the cells, and identified nearly 600 genes that had activity different from cells taken from people without schizophrenia.. Only about a quarter of these 600 genes had already been identified in studies of postmortem tissue.

The team then tested five known schizophrenia drugs to see whether they could restore the cells’ connectivity. After three weeks of treatment, only one drug, the antipsychotic loxapine, improved connectivity in all of the patients’ cells. Gage says the cells could even be used to test how individual patients might respond to specific treatments.

“This study illustrates that iPS cells could be really useful models to study these diseases at the cellular and molecular levels,” says Kim. However, questions remain about how well these cells represent neurons in living brains. He says that further research should focus on creating iPS cells using newer techniques that don’t genetically alter cells, and differentiating them into more specific types of neurons.