New findings on activity of two key neurotransmitter receptors in patients with schizophrenia brings researchers closer to understanding the molecular mechanisms that generate disease symptoms, according to an article published online June 11 by Nature Medicine.

US researchers examined neuronal receptor activity in postmortem brain tissue from patients with schizophrenia and patients without psychiatric disease. 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 the two receptor groups, suggesting a mechanism for the decrease in NMDA receptor function that has long been suspected in schizophrenia.

Previous studies of brains of patients with schizophrenia suggest altered function in the prefrontal cortex. 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 susceptibility to the disease.

Chang-Gyu Hahn, MD, PhD, Assistant Professor of Psychiatry and colleagues took a new approach to use NRG1 protein to activate its neuronal receptor, erbB4, to measure molecular response in postmortem brain tissue.

The binding of NRG1 to erbB4 stimulates neuronal receptor activity by phosphorylating molecules to the site of the receptor. The activation of erbB4, triggers 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 the glutamate receptor NMDA. 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.

"The fact that our studies of the brains of patients with schizophrenia demonstrate both erbB4 receptor overactivity as well as NMDA underactivity suggests the existence of a relationship between these two receptor groups," explains Hahn. "Altered NRG1-erbB4 signaling may contribute to NMDA receptor hypofunction in schizophrenia."

This finding is the first to display NMDA receptor hypofunction in the brains of patients with schizophrenia.ErbB4 and NMDA receptors are located at the post-synaptic junction, or the chemical receiving end of the neuron. Both, erbB4 and NMDA receptors are bound to scaffolding proteins called post-synaptic density (PSD), which can bridge receptor groups together and enhance their interactions.
"PSD proteins can act like a raft in the ocean," explains Hahn. "Just as holding onto a raft increases one's chance of survival, by binding onto PSD proteins, NMDA and erbB4 receptors can enhance their activity.”