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More than 100 genes were affected by the DISC1 variation. "This is the first indication that DISC1 regulates the activity of a large number of genes, many of which relate to synapses." Guo-li Ming, M.D., Ph.D., the Johns Hopkins University School of Medicine.

Mental illness-linked genes reduce synapses

A genetic variation linked to schizophrenia, bipolar disorder and severe depression wreaks havoc on connections among neurons in the developing brain, a team of researchers reports.

The study, led by Guo-li Ming, M.D., Ph.D., and Hongjun Song, Ph.D., of the Johns Hopkins University School of Medicine and described in the journal Nature, used 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.

The results add to evidence that several major mental illnesses have common roots in faulty "wiring" during early brain development.

"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," says Ming. "We found the most convincing evidence yet that the answer lies in the synapses that connect brain cells to one another."

Previous evidence for the relationship came from autopsies and from studies suggesting that some genetic variants that affect synapses also increase the chance of mental illness. But those studies could not show a direct cause-and-effect relationship, Ming says.

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 (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 just a few deleted DNA "letters" affects the developing brain, researchers collected skin cells from families with neither the variation nor mental illness, as well as from families with the variation and mental illness. They also collected samples from a healthy, unrelated person.

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 DISC1 variation.

In one of the cell lines with the DISC1 variation, graduate student Ha Nam Nguyen swapped out the DISC1 gene for a healthy version. He also inserted the disease-causing variation into one healthy cell line, as well as into the unrelated control cell line. Cell lines without the variation grew a normal amount of synapses, while those with the inserted mutation had only half that number.

"We had our definitive answer to whether this DISC1 variation is responsible for the reduced synapse growth," Ming says.

Researchers also compared the activity levels of genes in healthy neurons to neurons with the gene variation. To their surprise, they found more than 100 genes were affected by the DISC1 variation. "This is the first indication that DISC1 regulates the activity of a large number of genes, many of which relate to synapses," Ming added.

The research team is now looking more closely at other genes linked to mental disorders.

Abstract
Dysregulated neurodevelopment with altered structural and functional connectivity is believed to underlie many neuropsychiatric disorders1, and ‘a disease of synapses’ is the major hypothesis for the biological basis of schizophrenia2. Although this hypothesis has gained indirect support from human post-mortem brain analyses2, 3, 4 and genetic studies5, 6, 7, 8, 9, 10, little is known about the pathophysiology of synapses in patient neurons and how susceptibility genes for mental disorders could lead to synaptic deficits in humans. Genetics of most psychiatric disorders are extremely complex due to multiple susceptibility variants with low penetrance and variable phenotypes11. Rare, multiply affected, large families in which a single genetic locus is probably responsible for conferring susceptibility have proven invaluable for the study of complex disorders. Here we generated induced pluripotent stem (iPS) cells from four members of a family in which a frameshift mutation of disrupted in schizophrenia 1 (DISC1) co-segregated with major psychiatric disorders12 and we further produced different isogenic iPS cell lines via gene editing. We showed that mutant DISC1 causes synaptic vesicle release deficits in iPS-cell-derived forebrain neurons. Mutant DISC1 depletes wild-type DISC1 protein and, furthermore, dysregulates expression of many genes related to synapses and psychiatric disorders in human forebrain neurons. Our study reveals that a psychiatric disorder relevant mutation causes synapse deficits and transcriptional dysregulation in human neurons and our findings provide new insight into the molecular and synaptic etiopathology of psychiatric disorders.

Other authors on the paper are Ziyuan Guo and Gong Chen of The Pennsylvania State University; Matthew A. Lalli, Elmer Guzman and Kenneth S. Kosik of the University of California, Santa Barbara; Xinyuan Wang, Yijing Su, Nam-Shik Kim, Ki-Jun Yoon, Jaehoon Shin, Ce Zhang, Georgia Makri, David Nauen, Huimei Yu, Cheng-Hsuan Chiang, Jizhong Zou, Kimberly M. Christian, Linzhao Cheng, Christopher A. Ross, Nadine Yoritomo and Russell L. Magolis of The Johns Hopkins University; and Kozo Kaibuchi of Nagoya University Graduate School of Medicine in Japan.

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