The biological basis of schizophrenia is not fully understood, but new research by HHMI international research scholar Michael Salter offers insights into the disruptions in brain chemistry that underlie the debilitating mental illness.
The constant chatter of critical inner voices, the nightmarish vacillation between reality and illusion, the pinballing of thoughts around the mind—the symptoms of schizophrenia are baffling and frustratingly difficult to treat. The disease is even more confounding because the biological basis of this debilitating mental illness is not fully understood.
Now research by Howard Hughes Medical Institute international research scholar Michael Salter and his colleagues offers new insights into the disruptions in brain chemistry that underlie schizophrenia. The findings are reported in the March 29, 2011, issue of Nature Medicine.
Ranked by the World Health Organization as the third-most disabling medical condition, after quadriplegia and dementia, schizophrenia is a complex brain disorder marked by disorganized speech and thinking and psychotic symptoms, such as hallucinations and delusions.
Our hope is that understanding the molecular mechanisms involved in schizophrenia will lead us in new directions for developing therapies with minimal side effects. It's also possible that different symptoms of schizophrenia have different neural mechanisms, so sorting out which molecules are associated with which symptoms is important.
Michael W. Salter
"There are treatments, but they're not as effective as we'd like, and they have undesirable side effects," says Salter, a senior scientist at the Hospital for Sick Children in Toronto and a professor at the University of Toronto. "Our hope is that understanding the molecular mechanisms involved in schizophrenia will lead us in new directions for developing therapies with minimal side effects. It's also possible that different symptoms of schizophrenia have different neural mechanisms, so sorting out which molecules are associated with which symptoms is important."
In experiments with mice and rats, Salter and his colleagues investigated the effects of two proteins, neuregulin and ErbB4, on a key group of molecules called the NMDA receptor. The receptors and proteins are abundant in the hippocampus, an area of the brain where certain biochemical abnormalities associated with schizophrenia appear. Neuregulin and ErbB4, partners in a biochemical signaling pathway, are of interest because variations in the genes that code for them have been linked to increased risk for schizophrenia.
The NMDA receptor, which plays a critical role in learning, memory, and some aspects of development, also has been implicated in schizophrenia. When people who do not have schizophrenia are given a drug that temporarily blocks the action of the NMDA receptor, their thinking becomes disordered and they have hallucinations, just as in schizophrenia.
Such observations have led to the idea that in schizophrenia, the NMDA receptor is working at too low of a level, perhaps suppressed by neuregulin-ErbB4 signaling. But the new findings by Salter and his team show the story is not that simple.
Contrary to expectation, Salter and colleagues found that activating the neuregulin-ErbB4 signaling pathway had no effect on overall NMDA receptor function. But that's not to say there was no effect at all. In the specific situation when the NMDA receptor is more active than usual—the very time in which it performs its critical duties related to learning and memory—neuregulin-ErbB4 signaling did dial down the receptor's elevated activity. Even then, however, the neuregulin-ErbB4 duo didn't act directly on the NMDA receptor. The pair quashed the activity of Src, an enzyme that enhances NMDA receptor activity. The team’s conclusion: It's not direct dysfunction of the NMDA receptor that causes problems associated with schizophrenia; it's dysregulation of the receptor by suppression of Src.
The prefrontal cortex is another part of the brain affected in schizophrenia, and the researchers found that neuregulin affected NMDA receptor activity, via Src, in that brain region as well. "It appears that we see the same mechanism in both brain regions that we tested," Salter says. "Are there other brain regions that show similar types of mechanisms? That's something we're working on."
One more intriguing finding relates to theta rhythm, an oscillating pattern of brain activity. Normally, brief episodes of theta rhythm activity in the hippocampus are essential for learning, memory, and processing of cognitive information. But in people with schizophrenia, that activity is impaired. The researchers found that neuregulin-ErbB4 signaling, acting through Src, dramatically disrupted neuronal responses during theta rhythm stimulation.
"So that leads us to think that maybe some of the alterations in brain rhythms, specifically theta rhythm, seen in patients with schizophrenia might be due to neuregulin-ErbB4-Src inhibition of NMDA receptor activity," Salter says.
The Src connection identified in the animal studies may help explain biochemical clues found at autopsy in the brains of people with schizophrenia, Salter notes. "Src is a protein kinase—an enzyme that puts phosphate groups on proteins. In the post-mortem brains of people with schizophrenia, there is less phosphorylation of one of the proteins that is a major component of the NMDA receptor, and Src would be one of the kinases that could do that,” he explains. “In addition, these studies have found evidence for increased neuregulin-ErbB4 signaling, so our study provides a link between the two, through Src suppression."
Taken together, the rodent and human findings suggest new approaches to treating schizophrenia by manipulating neuregulin-ErbB4 signaling, boosting Src, or suppressing the action of other enzymes that undo Src's work on the NMDA receptor. However, developing such therapies will be tricky, Salter cautions, because all the proteins involved have multiple roles in the body. Finding ways to alter their functions in specific contexts will be key.
Salter collaborated on the work with Graham Pitcher, Lorraine Kalia, David Ng, Nathalie Goodfellow, and Evelyn Lambe in Toronto and Kathleen Yee at the Tufts University School of Medicine.