A new study of stem cells has revealed how a genetic variation linked to schizophrenia, bipolar disorder and severe depression affects connections among neurons in the developing brain.
According to the study led by Guo-li Ming and Hongjun Song of the Johns Hopkins University School of Medicine, using stem cells generated from people with and without mental illness to observe the effects of a rare and pernicious genetic variation on young brain cells found that several major mental illnesses have common roots in faulty "wiring" during early brain development.
Ming said that 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 and they found the most convincing evidence yet that the answer lies in the synapses that connect brain cells to one another.
One difficulty in studying the genetics of common mental illnesses is that they are generally caused by environmental factors in combination with multiple gene variants, any one of which usually could not by itself cause disease. A rare exception is the gene known as disrupted in schizophrenia 1 (DISC1), in which some mutations have a strong effect. Two families have been found in which many members with the DISC1 mutations have mental illness.
To find out how a DISC1 variation with a few deleted DNA "letters" affects the developing brain, the research team collected skin cells from a mother and daughter in one of these families who have neither the variation nor mental illness, as well as the father, who has the variation and severe depression, and another daughter, who carries the variation and has schizophrenia. For comparison, they also collected samples from an unrelated healthy person. Postdoctoral fellow Zhexing Wen, Ph.D., coaxed the skin cells to form five lines of stem cells and to mature into very pure populations of synapse-forming neurons.
After growing the neurons in a dish for six weeks, collaborators at Pennsylvania State University measured their electrical activity and found that neurons with the DISC1 variation had about half the number of synapses as those without the variation.
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 variation and found that the activities of more than 100 genes were different and the researchers added that this is the first indication that DISC1 regulates the activity of a large number of genes, many of which are related to synapses.
The study was published online in the journal Nature.
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