Characterized by symptoms such as delusions, hallucinations, and trouble with thinking and concentration, schizophrenia is a chronic and mental disorder that affects how one interacts with their surroundings.
Current statistics show that schizophrenia affects about one percent of the world’s population, regardless of racial, ethnic or socioeconomic background.
While there is currently no cure for schizophrenia, research has continued to develop new ways of understanding this disease. In fact, researchers at Brigham and Women’s Hospital (BWH) in Boston have recently used induced pluripotent stem cells (iPSCs) and embryonic stem cells to develop 3-D cerebral organoids, which are artificially grown models of the brain.
They can then use the mini-brains to examine the neurodevelopmental effects of a mutation in the gene DISC1 (Disrupted-In-Schizophrenia 1).
iPSCs are a type of stem cell that are derived from adult skin or blood cells. They have been reprogrammed back into states in which they can develop into any type of human cell. BWH’s study was published in Translational Psychiatry on April 12, 2018.
There are major benefits to having 3-D mini-brains. One of them is that studying a 3-D mini-brain can help us understand the cellular and molecular mechanism in psychiatric diseases. They also allow researchers to study the consequences of disease-associated mutations on brain development, something that they could not accomplish with traditional 2-D cell cultures.
Tracy Young-Pearse, head of the Young-Pearse Lab at the Ann Romney Center for Neurologic Diseases at BWH, is the senior author of the study.
“Mini-brains can help us model brain development,”
Young-Pearse said, according to ScienceDaily. “Compared to traditional methods that have allowed us to investigate humancells in culture in 2-D, these cultures let us investigate the 3-D structure and function of the cells as they are developing, giving us more information than we would get with a traditional cell culture.”
DISC1 is one of few genes associated with schizophrenia and other mental illnesses, including severe depression and bipolar disorder. This was first discovered in a large Scottish family, whose DISC1 gene was disrupted by gene translocation and appeared to be linked to an increased risk for mental disorders.
The researchers demonstrated in their results that mini-brains with DISC1-mutation were morphologically different from normal mini-brains.
DISC1-mutated brains were shown to have more disorganized structures, specifically an increased number of small and disorganized rosettes in place of large rosette and ventricle-like structures.
They also discovered that the effects of increased Wnt signaling in mini-brains had similar morphological effects that DISC1-mutations have onnormal mini-brains. The Wnt signaling pathway plays a critical role in embryonic development by regulating aspects such as cell fate determination, cell migration and neural patterning.
This study’s results support the researchers’ hypothesis that mutation in DISC1 results in elevated Wnt signaling in neural progenitor cells. This elevated Wnt signaling can lead to morphological and neurodevelopmental differences that may alter cell fate and cell migration.
“By producing cerebral organoids from iPSCs we are able to carefully control these experiments. We know that any differences we are seeing are because of the DISC1-mutation that we introduced,” Young-Pearse said.
Furthermore, she emphasizes that their research provides evidence that strengthens the connection between DISC1-mutations and risks of mental disorders.
“By looking at how DISC1-mutations disrupt the morphology and gene expression of cerebral organoids, we are strengthening the link between DISC1-mutation and major mental illness, and providing new avenues for investigation of this relationship,” she said.