Identification of Genes Provides New Clues into the Causes of Schizophrenia and Bipolar Disorder

June 04, 2007

Adriana Bobinchock
Public Affairs

Belmont, MA - Researchers at Harvard-affiliated McLean Hospital have identified clusters of genes in the brains of patients with schizophrenia and bipolar disorder that help explain more precisely the differences between the two psychiatric disorders. The finding may one day lead to new treatments for both illnesses, according to a paper (PubMed) published in the current issue of the Proceedings of the National Academy of Sciences

     "We cannot say for sure that these are the genes that cause the illnesses, but it seems likely that in some way they may be related to susceptibility to one or the other of the disorders and that is important,'' said Francine M. Benes, MD, PhD, director of the McLean Hospital Program in Structural and Molecular Neuroscience, and lead author of the paper.

     Pinpointing the genes involved would be a step towards finding "smarter" treatments for the two psychiatric disorders. In many cases, the same drug or drugs are used to treat certain aspects of each illness, with less than ideal effectiveness.

     "We would like to be more specific,'' said Benes, who is also the William P. and Henry B. Test Professor in Psychiatry in the field of Neuroscience at Harvard Medical School and a member of the prestigious Institute of Medicine of the National Academy of Science. "What we need from the standpoint of clinical care are more specific forms of therapy. In order to define more specific types of drug treatment, we need to understand these illnesses at this level of cells and molecules. The findings of this paper bring us closer to that.''

     The post-mortem study looked at the brains of patients with schizophrenia and bipolar disorder, comparing them with each other and with those of normal brains. There were a total of 21 subjects with seven in each group.

     From prior studies, the researchers knew that there are defects in the functioning of GABA cells in the hippocampus, the region of the brain responsible for learning and memory, in patients with schizophrenia and bipolar disorder. Throughout the brain, cells synthesize and release GABA, an amino acid transmitter, that helps control the flow of information along complex brain circuits like those found in the hippocampus.

     Earlier studies in several laboratories have shown that there is decreased expression of a marker for GABA cells in the brains of both types of patients. Benes and her colleagues launched this latest study to determine what causes this decreased expression.

     Using a microscopic laser knife to dissect the hippocampus, the researchers were able to isolate tissue samples from six different areas of the hippocampus, including the area known to have the least expression of a GABA cell marker, called GAD67, in the brains of patients with schizophrenia and bipolar disorder.

     Then, using microarray-based gene expression profiling, the researchers identified genes from this area and ran them through a computer program that was able to compare them with all other genes that have already been identified by geneticists and molecular biologists.

     The result was the identification of 25 different genes that may be involved in the regulation of the GABA marker, GAD67, in the human hippocampus. Ten of these genes were identified in the brains of the bipolar patients, while another 12 were found in the brains of those with schizophrenia. None of these genes were found in the control brains.

     While the genes all came from the same region, the cluster identified in the brains of those with schizophrenia was different from the cluster found in the brains of those with bipolar disorder. "The patterns of gene expression were fundamentally different from each other,'' Benes said. The same type of cell is affected in the two disorders, but the mechanism involved is different.''

     Benes said the findings suggest that the differences in the mechanisms may reflect in some way the differences in the genes that make a person susceptible to either disorder in the first place.

     She said the study is leading towards an understanding of the endophenotypes of the two disorders-the differences in genes and their expression patterns that help define each illness and distinguish them from each other-at the molecular level and within a specific type of neuron.

     "We have not had this type of insight before,'' she said.

     The study is the latest in a series on the brains of those with schizophrenia done by Benes over the past 25 years. "I feel a great sense of satisfaction to see this work moving in this direction,'' she said.

     But much more work needs to be done, she said.

     "We need to understand more about the GABA cells and how they are functioning,'' she said. "We need to go back to the level of the circuitry and understand how GABA cells are influencing the flow of information through the hippocampus to other regions of the brain.''

     U.S. News & World Report consistently ranks McLean Hospital the nation's top psychiatric hospital. McLean is an affiliate of Harvard Medical School and Massachusetts General Hospital, and a member of Partners HealthCare.

Email this page