A biochemical pathway in the brain that may contribute to schizophrenia has been identified by a research team led by Michael Salter, M.D., Ph.D., professor of physiology at the University of Toronto, as well as senior scientists at the Hospital for Sick Children (SickKids).
The study, published in the March 27 advance online edition of Nature Medicine, has the potential to lead to improved therapeutic approaches for the 24 million people worldwide affected with this disorder, the authors asserted.
“This is a paradigm shift in the way that we view the neural mechanisms of schizophrenia,” said Salter. “With our discovery we have brought together in a new way pieces of the schizophrenia puzzle. We hope that the understanding we have put together will lead to new forms of treatment that are more effective than the ones that are currently available.”
The scientists observed two partner proteins, NRG1 and ErbB4, in mouse models and how they affect an important brain receptor known as the N-methyl D-aspartate glutamate receptor (NMDAR). Although NRG1 and ErbB4 have been genetically associated with schizophrenia, the new study finds they have a surprising link to NMDARs.
The NMDAR plays an important role in synapses — sites which allow communication between the brain’s billions of individual nerve cells. It was suspected that NMDARs were functioning in a suppressed manner during schizophrenia because drugs that block NMDARs trigger hallucinations and disordered thought.
It had been hypothesized that NRG1 and ErbB4 might generally suppress NMDAR function but the present study found this was not happening. Instead, scientists found that NRG1 and ErbB4 work together by inhibiting another protein called Src.
The link here is that Src normally boosts NMDAR function when needed, such as in learning and memory. However, investigators discovered that by blocking Src, NRG1 and ErbB4 selectively prevented that vital boost in NMDAR function.
Researchers also studied nerve cell responses during brain activity that mimicked normal brain oscillations known as theta rhythm. Theta rhythm activity—needed for learning and memory—is dysfunctional in individuals with schizophrenia. The scientists found that by acting through Src, NRG1 and ErbB4 greatly reduced the nerve cell responses to theta rhythm activity.
The research findings suggest new treatment approaches to schizophrenia by reversing the effects of NRG1 and ErbB4 through enhancing the Src boost of NMDARs.
“The tricky part is that all of these proteins are involved in other functions of the body; we can’t randomly enhance or inhibit them as this would lead to side effects,” Salter said. “The key will be to develop clever ways to target the proteins in the context of the synapse.”
Source: University of Toronto