Closing In on the Cellular Culprits of Schizophrenia

(Philadelphia, PA) – The cause of schizophrenia remains a mystery, despite the millions of dollars spent trying to discover which genes play a role in its etiology. In at least 10 populations around the world, a significant association between schizophrenia and the gene for dysbindin has been noted – making dysbindin the most highly replicated schizophrenia-associated gene described to date. Now, researchers at the University of Pennsylvania School of Medicine are starting to place where dysbindin fits in the pathway that leads from a gene to a psychiatric disorder. Schizophrenia affects between 1 to 2 percent of people worldwide during their lifetime and about 2.2 million American adults have schizophrenia in a given year.

Using quantitative immunohistochemistry in postmortem brain tissue, the Penn investigators found that the expression of dysbindin protein was reduced in more than 80 percent of the patients with schizophrenia by an average of 40 percent relative to matched healthy controls.(Click on the thumbnail image above to view the full-size photo). “This is among the most significant findings I’ve seen yet in schizophrenia postmortem research, and it represents a critical lead for understanding schizophrenia,” says senior author Steven Arnold, MD, Associate Professor of Psychiatry and Neurology. The research appears in the May issue of the Journal of Clinical Investigation.

The scientists also found that, in the same brain regions in which there was a decrease in dysbindin, there was also an increase in the amounts of presynaptic glutamate packets, or vesicles, and that these findings were highly correlated. Synaptic vesicles form at the ends of nerve cells and contain chemical neurotransmitters such as glutamate. Neurons communicate with each other by releasing neurotransmitters from these vesicles. The researchers surmise that dysbindin affects the manufacture or breakdown of these vesicles and, consequently, glutamate may not be released properly – thus impairing communication between neurons.

The abnormality was most prominent in the dentate gyrus portion of the hippocampus. This area of the brain is especially important for memory, which is known to be impaired in schizophrenia. The study’s findings were independently replicated, using two collections of postmortem brain tissue, one maintained by Penn and another by the Stanley Medical Research Institute.

“The next step is to understand what dysbindin does in the brain,” explains Arnold. “We’ve found that dysbindin abnormalities are part of schizophrenia, but we need to know much more to translate this information into practical knowledge to help patients. In other words, we need to know what other proteins dysbindin interacts with and whether it involves just glutamate or other neurotransmitters like serotonin, dopamine or GABA and how dysbindin affects the electrical activity of the brain. And, are there medicines that alter dysbindin expression in the brain?” To answer these and other important questions, Arnold and colleagues are currently collaborating with other researchers at the University of Oxford in the United Kingdom.

“One of the most exciting parts of this story is that the extensive work that has gone on in the genetics of schizophrenia is finally starting to bear fruit in terms of identifying specific genes that we can then follow-up in the brain,” says Arnold. “Who would have predicted that a protein that was first discovered a few years ago by muscular dystrophy researchers could have anything to do with schizophrenia? The genetics studies pinpointed a link between dysbindin and schizophrenia. This clue prompted us to investigate dysbindin in the brain where we found that it is highly expressed and highly abnormal in schizophrenia.”

Other Penn researchers collaborating on this work are Konrad Talbot, Wess L. Eidem, Edward W. Thompson, Rachel J. Smith, Chang-Gyu Hahn, John Q. Trojanowski, and Raquel E. Gur, as well as Caroline L. Tinsley and Matthew A. Benson from Oxford University. The research was supported in part by the National Institute of Mental Health.

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