In important new research, a team that included five past and present recipients of NARSAD Grants recreated human brain cells from skin cells of patients with a rare mutated version of a gene called DISC1. This mutation is known to be linked to schizophrenia, bipolar disorder and major depression. Much of the pathology found in human brain cells, in this study, affects the formation and regulation of synapses, the tiny gaps across which brain cells exchange messages. The new study helps confirm that schizophrenia is, at least in part, “a disease of synapses” and adds to evidence that several major mental illnesses have common roots in faulty "wiring" during early brain development.
Years ago, DISC1 was identified as a “risk gene”—i.e., a gene that when mutated confers a much higher-than-normal risk for developing a disease—for schizophrenia, bipolar disorder and major depression. But there have remained many difficult-to-answer questions about the influence of this gene. The new study led by Guo-li Ming, M.D., Ph.D., and Hongjun Song, Ph.D., of Johns Hopkins University, both of whom are recipients of NARSAD Independent Investigator Grants (Dr. Ming in 2010 and Dr. Song in 2008), begins to answer some important questions. Conducted in collaboration with colleagues from universities in the United States, China, and Japan, the results were published August 17th in the journal Nature.
This new work offered a new window to study the effect of the DISC1 mutation, moving beyond post-mortem brain sample and animal model studies. To see what goes wrong in cells from patients as they develop has long been a dream of scientists. It’s not possible to remove cells from the brains of living humans; but with this new iPSC (induced pluripotent stem cell) technology, it is possible to sample human skin cells and convert them to brain cells. Researchers are then able to watch the cells develop and to see what impact they have on brain function as the cells mature.
After growing the neurons in a dish for six weeks, the researchers measured their electrical activity and found that neurons with the DISC1 mutation had about half the number of synapses as those without the variation. It took them another two years of work to confirm this was caused by the DISC1 mutation.
“This was the next best thing to going back in time to see what happened while a person was in the womb to later cause mental illness,” said Dr. Ming. “We found the most convincing evidence yet that the answer lies in the synapses that connect brain cells to one another.”
To find out how DISC1 acts on synapses, the researchers also compared the activity levels of genes in the healthy neurons to those with the mutation. They found that the activities of more than 100 genes were different between the two groups. Among the abnormally “expressed” genes were 89 previously linked to schizophrenia, bipolar disorder, depression and other mental illnesses. “This is the first indication that mutant DISC1 regulates the activity of a large number of genes, many of which are related to synapses," Dr. Ming says.
The results suggest a common disease mechanism at work in several major mental illnesses, which brings together the issues of genetic risk, abnormal nerve cell development, and synaptic dysfunction. The approach the team used drew praise from Thomas R. Insel, M.D., director of the National Institute of Mental Health. “It serves as a model for linking genetic clues to brain development,” he said of the research.
The other NARSAD Grant recipients on the team were: Kimberly M. Christian, Ph.D., 2012 Young Investigator; Russell L. Margolis, M.D., 2003 Independent Investigator and 2007 Distinguished Investigator; Christopher A. Ross, M.D., Ph.D., 2004 Distinguished Investigator.