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New stem cell research points to early indicators of schizophrenia

Currently, over 1.1 percent of the world’s population has schizophrenia, with an estimated 3 million cases in the United States alone. The economic cost is high: in 2002, Americans spent nearly $63 billion on treating and managing the disability. The emotional cost is higher still: 10 percent of those with schizophrenia are driven to commit suicide.

Yet, scientists still know little about its underlying causes and do not know which cells in the brain are affected and how. Previously, it had only been possible to study schizophrenia by examining the brains of patients after death, but age, stress, medication or drug abuse had often altered or damaged the brains, making it difficult to pinpoint the disease’s origins.

Fred Gage and Kristen Brennand

Using new stem cell technology, scientists in the lab of Fred Gage have shown that neurons generated from the skin cells of people with schizophrenia behave strangely in early developmental stages. The findings of the study, published in Molecular Psychiatry, are consistent with a prevailing theory that events during pregnancy can contribute to schizophrenia, even though the disease doesn’t manifest until early adulthood.

“This study aims to investigate the earliest detectable changes in the brain that lead to schizophrenia,” says Gage, who heads Salk’s Engman Laboratory for Schizophrenia Research. “We were surprised at how early in the developmental process defects in neural function could be detected.”

Taking skin cells from patients, Gage’s team coaxed the cells to revert back to an earlier stem cell form and then prompted them to grow into very early stage neurons (dubbed neural progenitor cells or NPCs), which are similar to the cells in the brain of a developing fetus. They generated NPCs from the skin cells of four patients with schizophrenia and six people without the disease, then tested the cells in two types of assays. On both tests, the researchers found that NPCs from people with schizophrenia differed in significant ways from those taken from unaffected people.

These images show the movement of patient-derived neural progenitor cells from a sphere of neurons in a migration assay. How far and how quickly the neurons move indicates whether they may behave atypically in the brain.

Kristen Brennand, the paper’s first author and now an assistant professor at the Icahn School of Medicine at Mount Sinai, said the researchers were surprised that the skin-derived neurons remained in such an early stage of development. “We realized they weren’t mature neurons but only as old as neurons in the first trimester,” she says. “So we weren’t studying schizophrenia but the things that go wrong a long time before patients actually get sick.”

According to Gage, the study hints that there may be opportunities to create diagnostic tests for schizophrenia at an early stage. The research was supported in part by the Robert and Mary Jane Engman Foundation.