Mouse Study May Yield Insight, New System for Drug Testing
People with schizophrenia have an alteration in a pattern of brain electrical activity associated with learning and memory. Now, researchers from the National Institutes of Health and Sweden’s Karolinska Institute have identified in mouse brain tissue a molecular switch that, when thrown, increases the strength of this electrical pattern.
The researchers found that adding the brain chemical Neuregulin-1 to the brain tissue boosted the electrical signals that the tissue generated.
“This finding may yield new insights into a form of altered brain activity occurring in schizophrenia,” said Duane Alexander, M.D., director of NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). “It may also lead to new methods for screening drugs with potential as schizophrenia treatments.”
The findings appear online in the journal Cerebral Cortex. The research was conducted by Andre Fisahn, Ph.D, of the Karolinska Institute, in collaboration with Andres Buonanno, Ph.D, and his colleagues in NICHD’s section on Molecular Neurobiology. Dr. Buonanno was the study’s senior author.
Schizophrenia affects about 1.1 percent of the U.S. population. Symptoms include delusions, hallucinations, disordered thinking and social withdrawal.
As nerve impulses travel through the brain, they emit weak electrical signals that can be measured through sensors attached to the scalp. The different parts of the brain emit different kinds of electrical signals. These signals vary with the kinds of mental activity taking place within the brain.
Dr. Buonanno and his colleagues studied electrical patterns known as gamma oscillations. Ordinarily, gamma oscillations occur when people are involved with learning and memory tasks, Dr. Buonanno said. In people with schizophrenia, however, the strength of the gamma oscillations is reduced.
“With schizophrenia, the gamma oscillations are fainter,” Dr. Buonanno said. “It’s analogous to tuning in the weak signal of a distant station on your car radio, as opposed to picking up the strong signal of a station that’s nearby.”
Dr. Buonanno and his colleagues studied brain sections from the hippocampus, a brain region involved in learning and memory. The hippocampus also is a major source of gamma oscillations.
The researchers first chemically stimulated the brain sections, in effect jump starting them so that they began generating gamma oscillations. After the researchers exposed the sections to Neuregulin-1, the strength of the gamma oscillations increased dramatically.
Like a key fits into a lock, Neuregulin-1 fits into a special site, or receptor, on the surface of brain cells. Specifically, Neuregulin-1 binds to the receptor known as ERB4.
Further tests confirmed the role of Neuregulin-1 in boosting gamma oscillations. The researchers soaked the hippocampus sections in a drug that blocks ERB4. When the researchers added Neuregulin-1, the hippocampus sections did not show an increase in gamma oscillations.
Similarly, the researchers then added Neuregulin-1 to hippocampus sections of mice that were genetically incapable of producing the ERB4 receptor. Once again the animals’ brains failed to show any increase in gamma oscillations.
The researchers chose to study Neuregulin-1 and ERB4 because earlier studies had shown that people with schizophrenia often have alterations in the genes that contain the information needed to make these substances.
“For the first time, we were able to show that Neuregulin-1, which has been genetically implicated in schizophrenia, affects a brain activity that appears to be altered in schizophrenia,” Dr. Buonanno said.
In addition, the researchers found that ERB4 receptors were abundant on a particular type of neuron (a specialized cell involved in the transmission of information). Known technically as parvalbumin expressing neurons, these neurons slow the transmission of electrical signals through the brain.
Studies performed at autopsy have found that people with schizophrenia have fewer parvalbumin expressing neurons than do people who do not have schizophrenia. In their study, Dr. Buonanno and his colleagues reported that the mice which were genetically incapable of producing the ERB4 receptor also have fewer parvalbumin expressing neurons than do genetically normal mice.
“Our study has uncovered an interesting lead,” Dr. Buonanno said. “Future studies of brain regions rich in ERB4 receptors may yield important information on the nature of schizophrenia.”
Dr. Buonanno added that studies of how various drugs affect the ERB4 receptor and parvalbumin expressing neurons may lead to novel drug treatments for schizophrenia.
Other authors of the study were Jorg Neddens and Leqin Yan, also of the NICHD Section on Molecular Neurobiology.
Information on schizophrenia is available from NIH’s National Institute of Mental Health at http://www.nimh.nih.gov/health/publications/schizophrenia.
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The NICHD sponsors research on development, before and after birth; maternal, child, and family health; reproductive biology and population issues; and medical rehabilitation. For more information, visit the Institute’s Web site at http://www.nichd.nih.gov/.
The National Institutes of Health (NIH) — The Nation's Medical Research Agency — includes 27 Institutes and Centers and is a component of the U. S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical, and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.