It affects over 1.1% of the world's population and 3 million people in the US alone, yet the underlying causes of schizophrenia still largely elude scientists. Now, researchers from the Salk Institute in California have demonstrated that neurons from skin cells of patients with schizophrenia behave oddly in early stages of development, supporting the theory that schizophrenia begins in the womb.
The researchers, who published their results in the journal Molecular Psychiatry, say their findings could provide clues for how to detect and treat the disease early.
Schizophrenia is a chronic, severe mental disorder marked by disorders in thought processes, perceptions and emotions. Some symptoms include delusions, hallucinations, lack of desire to form social relationships and blunted emotions.
According to the study authors, the financial and emotional costs of the disease are quite high. In 2002 alone, Americans spent around $63 billion on treating and managing the condition, and 10% of those with schizophrenia commit suicide after being unable to cope with it.
In previous studies, investigators had only been able to study schizophrenia in the brains of deceased patients, but it was difficult to identify the origin of the disease, as age, stress, medication or drug abuse can alter or damage the patients' brains.
Prof. Fred H. Gage, professor of genetics from Salk, says:
"This study aims to investigate the earliest detectable changes in the brain that lead to schizophrenia. We were surprised at how early in the developmental process that defects in neural function could be detected."
Schizophrenia-inclined cells had poor migration and oxidative stress
By using stem cell technology, the researchers were able to study schizophrenia in a new way; they took skin cells from patients, induced the cells to revert back to an earlier stem cell form and then encouraged them to grow into neural progenitor cells (NPCs), which are early-stage neurons.
This image shows movement of patient-derived NPCs from a sphere of neurons. How far and how quickly the neurons move tells whether they may behave abnormally in the brain.
Image credit: Salk Institute for Biological Studies
The team explains that NPCs are similar to cells in a developing fetus' brain. In total, the investigators created NPCs from four patients with schizophrenia and six without the condition.
Next, they examined how far the cells moved and interacted with specific surfaces, and then they assessed cell stress by imaging mitochondria - the tiny organelles that generate cell energy.
Overall, the team observed that NPCs from people with schizophrenia differed significantly from those of people without the disease. In detail, cells from patients with schizophrenia exhibited strange activity in two classes of proteins, which are involved in adhesion and connectivity, and oxidative stress.
Additionally, the cells from people with schizophrenia had "aberrant migration," which the researchers say could result in poor connectivity later seen in the brain, and increased levels of oxidative stress, which can result in cell death.
Commenting on their findings, Kristen Brennand, first author and assistant professor at Icahn School of Medicine at Mount Sinai, says she and her team were surprised the neurons stayed in such an early development stage, adding:
"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."
She and her team say their findings line up with a popular theory that occurrences during pregnancy can lead to schizophrenia, even though it does not appear until early adulthood.
Potential for diagnostic tests at early stages
The researchers say other studies have suggested that mothers who experience extreme stress, infections or malnutrition during pregnancy have a higher risk of having children with the condition, however, the reason for this is unknown.
Prof. Gage says their study "hints that there may be opportunities to create diagnostic tests for schizophrenia at an early stage."
When they studied the effects of antipsychotic medications - such as clozapine and loxapine - they found they did not improve migration in NPCs, and loxapine actually worsened migration.
Brennand says this was the opposite of what they expected. "Though in hindsight, using drugs that treat symptoms might not be helpful in trying to prevent the disease," she adds.
They conclude their study by noting that though their methods and findings could be used to pinpoint new cellular phenotypes of schizophrenia, they "caution that, because of our small sample size, these phenotypes may not generalize across all [schizophrenia] patients."
As such, they plan to increase their sample size in future studies in order to assess a wider range of patients.