Researchers at the University of Pennsylvania School of Medicine, in collaboration with scientists at the City University of New York, have identified a striking dysregulation in neuronal receptor activity in the postmortem brain tissue from patients with schizophrenia.
By stimulating receptors in the prefrontal cortex, the research team tracked heightened levels of erbB4 receptor activity, as well as decreased NMDA receptor activity in the tissue from patients with schizophrenia. Additionally, they were able to identify a relationship between these two receptor groups, suggesting a mechanism for decreased NMDA receptor function that has long been suspected in schizophrenia. The researchers report their findings in Nature Medicine.
Schizophrenia, a mental disorder afflicting approximately one percent of the world population, is characterized by a variety of symptoms such as: hallucinations, paranoia, disorganized behavior and the inability to experience pleasure. Previous studies of the brains of patients with schizophrenia suggest altered function in the prefrontal cortex, the brain's organizational center for cognitive function, personality expression, and behavioral control. International, large-scale genetic studies of patients with schizophrenia have pointed researchers to a gene called neuregulin 1 (NRG1), which appears to play a role in determining one's susceptibility to the disease.
Chang-Gyu Hahn, M.D., Ph.D., Assistant Professor of Psychiatry, Steven Arnold, M.D., Associate Professor of Psychiatry and Neurology, and Raquel Gur, M.D., Ph.D., Professor of Psychiatry, and colleagues at Penn, in collaboration with Hoau-Yan Wang, Ph.D., at The City University of New York, took an approach to use NRG1 protein to activate its neuronal receptor, erbB4, to measure the molecular response in postmortem brain tissue.
The binding of NRG1 to erbB4 stimulates neuronal receptor activity by adding phosphate molecules to the site of the receptor. The activation of erbB4, in turn, kicks off a cascade of molecular events within the neuron. When comparing the initial steps of neurochemical activity in postmortem brain tissue of mentally healthy patients to those with schizophrenia, the researchers discovered that NRG1-erbB4 activity was significantly greater in the brains of patients with schizophrenia.
Hahn and colleagues also studied a second neuron receptor called NMDA, which receives input from the neurotransmitter glutamate. Previous studies at other labs have demonstrated the relationship between erbB4 and NMDA receptor activity and have led researchers to believe that enhanced activity of erbB4 receptors results in a decrease in NMDA receptor activity.
Low levels of NMDA receptor activity are believed to contribute to symptoms of schizophrenia. By stimulating NMDA receptors with glutamate, and measuring the subsequent changes in phosphorylation at the receptor, Penn scientists were able to track an impairment in NMDA receptor activation in the postmortem brain tissue from patients with schizophrenia.