Stem-Cell-Based “Disease in a Dish” Studies Add to Evidence That Major Mental Illnesses Are Based on Faulty Neural Wiring

Researchers have long suspected that major mental disorders are genetically-rooted diseases of synapses – the connections between neurons. Now, investigators, supported in part by the National Institutes of Health, have demonstrated in patients' cells how a rare mutation in a suspect gene disrupts the turning on and off of dozens of other genes underlying these connections. "Our results illustrate how genetic risk, abnormal brain development, and synapse dysfunction can corrupt brain circuitry at the cellular level in complex psychiatric disorders," explained Hongjun Song, Ph.D. , of Johns Hopkins University, Baltimore, a grantee of the NIH's National Institute of Mental Health (NIMH), a funder of the study. Dr. Song and colleagues, from universities in the United States, China, and Japan, report on their discovery in Nature, August 17, 2014. "The approach used in this study serves as a model for linking genetic clues to brain development," said NIMH director Thomas R. Insel, M.D. Most major mental disorders, such as schizophrenia, are thought to be caused by a complex interplay of multiple genes and environmental factors. However, studying rare cases of a single disease-linked gene that runs in a family can provide shortcuts to discovery. Decades ago, researchers traced a high prevalence of schizophrenia and other major mental disorders – which often overlap genetically – in a Scottish clan to mutations in the gene DISC1 (Disrupted In Schizophrenia-1). But until now, most of what's known about cellular effects of such DISC1 mutations has come from studies in the rodent brain. To learn how human neurons are affected, Dr. Song's team used a disease-in-a-dish technology called induced pluripotent stem cells (iPSCs). A patient's skin cells are first induced to revert to stem cells.
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