Researchers from the Lieber Institute for Brain Development have used organoids to identify a developmental problem found early in life in the brains of people who later have schizophrenia. Their findings may present a new potential drug target for therapies to treat schizophrenia. The study also validates their approach as a model for other scientists to study the disease. Their work was published Nov. 2 in the American Journal of Psychiatry. Read the paper.
A team of scientists, including Lieber Institute Investigator and senior author Jennifer Erwin, Ph.D., used novel techniques to grow organoids—basically, 3D mini-brains—to replicate and study the early stages of brain development.
“We wanted to know what’s different in the brains of schizophrenic vs. nonschizophrenic individuals,” explains Dr. Erwin. “The problem with the brains of people who have schizophrenia is that they have lived the life of a schizophrenic individual. Maybe they were taking antipsychotics, or they smoked. All that is reflected in the brain tissue we look at.”
The researchers wanted to turn back the clock and examine the brain tissue of people with schizophrenia before environmental factors have affected their genes. They turned to the Lieber Institute’s brain repository, a collection of more than 4,300 brains donated with consent from family members. The donated brains include those from people diagnosed with schizophrenia and other neurodevelopmental disorders, as well as healthy controls. The repository holds samples of both the brain and dura, the leathery lining that covers the brain and spinal cord.
Dr. Erwin and her team, including first author Tomoyo Sawada, Ph.D., a Lieber Institute Research Scientist, used samples of the dura to derive induced pluripotent stem cells (iPSCs) from schizophrenia patients. Such stem cells can be differentiated to become any cell in the body. Dr. Erwin, Dr. Sawada and their colleagues used the stem cells to create ventral forebrain organoids, tiny mini-brains to replicate that specific area of the brain.
For the first time, the researchers were able to compare the findings from the organoids with the actual postmortem brain tissues from the same donors. Their unique approach allowed them to validate whether the lab-grown organoids mirror the gene expression changes they saw in the brain tissue of the corresponding adult donors with schizophrenia.
The scientists found consistencies in gene expression between the organoids and the brain tissue, including a previously unknown developmental problem in the striatal region of the brain. The striatum is a central component of the basal ganglia and is critical for sensorimotor, cognitive and emotional processes. Interestingly, most antipsychotic treatments target D2 dopamine receptors primarily located in the striatum.
“While brain organoids simulate early human brain development, they are simpler than the real human brain,” says Dr. Sawada. “Also, it’s worth noting our study had a limited sample size, which may not fully account for the genetic variability in the broader population.”
The Lieber Institute team hopes to expand on their work by studying a larger group of subjects and evaluating compounds that could target the developmental issues they found in the striatum. Very targeted therapies would avoid the side effects associated with typical antipsychotics.