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Schizophrenia Genetics Linked to Disruption in How Brain Processes Sound

Recent studies have identified many genes that may put people at risk for schizophrenia. But what links genetic differences to changes in altered brain activity in schizophrenia is not clear. Now, three laboratories at the Perelman School of Medicine at the University of Pennsylvania have come together, using electrophysiological, anatomical, and immunohistochemical approaches - along with a unique high-speed imaging technique - to understand how schizophrenia works at the cellular level, especially in identifying how changes in the interaction between different types of nerve cells lead to symptoms of the disease. The findings were reported online on October 3, 2011 in the Proceedings of the National Academy of Sciences. "Our work provides a model linking genetic risk factors for schizophrenia to a functional disruption in how the brain responds to sound, by identifying reduced activity in special nerve cells that are designed to make other cells in the brain work together at a very fast pace," explains lead author Dr. Gregory Carlson, assistant professor of Neuroscience in Psychiatry. "We know that in schizophrenia this ability is reduced, and now, knowing more about why this happens may help explain how loss of a protein called dysbindin leads to some symptoms of schizophrenia." Previous genetic studies had found that some different forms of the gene for dysbindin were found in people with schizophrenia. Most importantly, a prior finding at Penn showed that the dysbindin protein is reduced in a majority of schizophrenia patients, suggesting it is involved in a common cause of the disease. For the current PNAS study, Dr. Carlson, Dr. Steven J. Siegel, associate professor of Psychiatry, director of the Translational Neuroscience Program; and Dr. Steven E. Arnold, director of the Penn Memory Center, used a mouse with a mutated dysbindin gene to understand how reduced dysbindin protein may cause symptoms of schizophrenia. The team demonstrated a number of sound-processing deficits in the brains of mice with the mutated gene. They discovered how a specific set of nerve cells that control fast brain activity lose their effectiveness when dysbindin protein levels are reduced. These specific nerve cells inhibit activity, but do so at an extremely fast rate, essentially turning large numbers of cells on and off very quickly in a way that is necessary to normally process the large amount of information travelling into and around the brain. Other previous work at Penn, in the lab of Dr. Michael Kahana, had shown that in humans the fast brain activity that is disrupted in mice with the dysbindin mutation is also important for short-term memory. This type of brain activity is reduced in people with schizophrenia and resistant to current therapy. Taken as a whole, this work may suggest new avenues of treatment for currently untreatable symptoms of schizophrenia, says Dr. Carlson. Additional co-authors of the current study are: Drs. Konrad Talbot, Tobias B. Halene, Michael J. Gandal, Hala A. Kazi, Laura Schlosser, Quan H. Phung, and Raquel E. Gur, all from the Department of Psychiatry at Penn. [Press release] [PNAS abstract]