Neurons generated from the skin cells of schizophrenia patients behave strangely in the early developmental stages, offering clues that might lead to earlier detection and treatment, according to scientists from the Salk Institute.
The study, published in the journal Molecular Psychiatry, supports the theory that the neurological dysfunction that eventually leads to schizophrenia may begin in the brains of fetuses.
“This study aims to investigate the earliest detectable changes in the brain that lead to schizophrenia,” said Fred H. Gage, Ph.D., professor of genetics at Salk. “We were surprised at how early in the developmental process that defects in neural function could be detected.”
Up until now, scientists could only study the disease by examining the brains of cadavers; but age, stress, medication, or drug abuse had often changed or damaged these brains, making it harder to figure out the where it all began.
The Salk scientists were able to go around this obstacle by using stem cell technologies. They took skin cells from patients, coaxed the cells back to an earlier stem cell form and then prompted them to grow into very early-stage neurons called neural progenitor cells (NPCs). These NPCs are similar to cells found in the brain of a fetus.
The researchers tested the cells in two ways: In one test, they looked at how far the cells moved and interacted with particular surfaces; in the other test, they looked at cell stress by imaging mitochondria, tiny organelles that generate energy for the cells.
On both tests, the NPCs from schizophrenia patients differed in significant ways from those taken from people without the disease.
In particular, cells taken from people with schizophrenia showed unusual activity in two major classes of proteins: those involved in adhesion and connectivity, and those involved in oxidative stress. Schizophrenia neural cells seemed to have aberrant migration (which may result in the poor connectivity seen later in the brain) and greater levels of oxidative stress.
These results support the current theory that events during pregnancy can contribute to schizophrenia, even though symptoms typically don’t begin until early adulthood. For example, previous research suggests that pregnant mothers who experience infection, malnutrition, or extreme stress are at greater risk of having children with schizophrenia.
“The study hints that there may be opportunities to create diagnostic tests for schizophrenia at an early stage,” said Gage.
First author Kristen Brennand, Ph.D., assistant professor at 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 said. “So we weren’t studying schizophrenia but the things that go wrong a long time before patients actually get sick.”
The researchers also found that antipsychotic medication (such as clozapine and loxapine) did not improve migration in NPCs (loxapine actually made it worse).
“That was an experiment that gave the opposite results from what we were expecting,” says Brennand. “Though in hindsight, using drugs that treat symptoms might not be helpful in trying to prevent the disease.”
Source: Salk Institute