Stem cell techniques yield new clues to the origins of schizophrenia

Although the word “schizophrenia” was coined over 100 years ago, scientists are still stumped by what causes this severe brain disorder, which afflicts an estimated three million Americans and presents a financial burden of $63 billion each year. People with schizophrenia suffer debilitating delusional and hallucinatory symptoms, such as hearing voices or believing that tragedy is imminent. Life-long drug treatment and psychotherapy can help keep symptoms in check—but ten percent still surrender to the disease by taking their own lives.

Studying the brains of schizophrenic patients after death reveals abnormalities in brain cells. But these defects seen at the end of life tell very little about what initiates the disease or predisposes someone to it. Clearly new approaches are needed to tackle schizophrenia.

Sounds like a job for stem cells.

In fact, results published this week reveal just that. In a study published by CIRM grantees at the Salk Institute and their collaborators in Molecular Psychiatry report on using stem cell techniques to glimpse early hallmarks of schizophrenia in stem-cell derived brain cells that resemble those of the developing brain.

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As an initial pilot study, the researchers collected skin samples from four people with schizophrenia and six individuals without the disease and then reprogrammed those skin cells into embryonic-like stem cells. From there, they transformed the stem cells into immature brain cells called neural precursor cells, or NPCs.

With the NPCs in hand, the researchers ran two analyses that can look for differences in a vast array of genes and proteins in the schizophrenia (SZ)-derived cells compared to non-SZ cells. Both tests indicated abnormal gene activity and protein levels related to cell movement and cell stress in the SZ cells. And as predicted by these molecular tests, examination of cell function showed that the SZ-derived NPCs indeed had poor cell migration, which could lead to abnormal communication among brain cells and increased cell stress which could stimulate brain cell death.

These results are in line with previous studies that suggest schizophrenia begins during early fetal brain development—possibly due to extreme stress or infection during pregnancy. In a Salk Institute press release picked up by Health Canal first author Kristen Brennand, assistant professor at Icahn School of Medicine at Mount Sinai in New York, spoke about the advantage of using these NPCs:

We realized they weren’t mature neurons but only as old as neurons in the first trimester. So we weren’t studying schizophrenia but the things that go wrong a long time before patients actually get sick.

And since the gene and protein tests used in this pilot study are highly scalable, the logical next step is to perform the analysis on hundreds or thousands of patient samples to better reflect the complexity and variation in the disease. As senior author Fred Gage, a CIRM grantee and professor at the Salk Institute, points out in the press release:

The study hints that there may be opportunities to create diagnostic tests for schizophrenia at an early stage.

For more from Dr. Gage about modeling disease with stem cells, check out this video from our stem cell basics series.

CIRM Funding: New Cell Lines Award: RL1-00649

Todd Dubnicoff

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