University of Maryland School of Medicine Researchers Find Novel Chemical Switch That May Help Decrease Crucial Symptoms of Schizophrenia

Research in Mice Could Have Implications for Human Brain Disease

A new study by University of Maryland School of Medicine researchers has found that in mice, adjusting levels of a compound called kynurenic acid can have significant effects on schizophrenia-like behavior. The study appeared in the latest issue of the journal Biological Psychiatry.

In recent years, scientists have identified kynurenic acid as a potential key player in schizophrenia. People with schizophrenia have higher than normal levels of kynurenic acid in their brains. KYNA, as it is known, is a metabolite of the amino acid tryptophan; it decreases glutamate, and research has found that people with this illness tend to have less glutamate signaling than people without the disease. Scientists have theorized that this reduction in glutamate activity, and therefore the higher KYNA levels seen in patients, might be connected with a range of symptoms seen in schizophrenia, especially cognitive problems.

For several years, Robert Schwarcz, PhD, a Professor in the Department of Psychiatry at the University of Maryland School of Medicine (UM SOM), who in 1988 was the first to identify the presence of KYNA in the brain, has studied the role of KYNA in schizophrenia and other neuropsychiatric diseases.

For the new study, Dr. Schwarcz and his team collaborated closely with scientists at the Karolinska Institute in Stockholm, Sweden, the University of Leicester in the United Kingdom, and KynuRex, a biotech company in San Francisco.

“This study provides crucial new support for our longstanding hypothesis,” Dr. Schwarcz said. “It explains how the KYNA system may become dysfunctional in schizophrenia.”

Dr. Schwarcz and his colleagues studied mice which were deficient in kynurenine 3-monooxygenase, or KMO, an enzyme that is crucial for determining the levels of KYNA in the brain. Specifically, lower KMO results in higher levels of KYNA. Interestingly, patients with schizophrenia have lower than normal brain levels of KMO, which may be linked to lower levels of glutamate.

The mice with lower levels of KMO showed impairments in contextual memory and spent less time than did a control group interacting with an unfamiliar mouse in a social setting. The low-KMO mice also showed increased anxiety-like behavior when put into a maze and other challenging settings. Since these behaviors are similar to behavioral traits in humans with schizophrenia, this suggests that KMO and KYNA may play a key role in the disease.

The new discovery has clinical implications as well. On its own, boosting glutamate on a large scale has serious side effects, including seizures and nerve cell death. Dr. Schwarcz and his colleagues propose that modifying KYNA could adjust glutamate more precisely. In recent years, he and his collaborators have in fact shown that a reduction in KYNA improves cognition in animals that have cognitive deficits similar to those seen in schizophrenia. Because this mechanism is indirect, it seems not to trigger the same side effects that directly boosting glutamate does. His UM SOM team is now investigating compounds that might produce the same results in humans.

“Dr. Schwarcz’s work illustrates how our school is making groundbreaking advances on the most difficult problems,” said UM SOM Dean E. Albert Reece, MD, PhD, MBA, who is also the vice president for Medical Affairs, University of Maryland, and the John Z. and Akiko K. Bowers Distinguished Professor. “These findings hold out the promise of a much clearer understanding of the molecular mechanisms that underlie this complex and agonizing disease.”

About the University of Maryland School of Medicine

Celebrating its 210th anniversary, the University of Maryland School of Medicine was chartered in 1807 as the first public medical school in the United States. It continues today as an innovative leader in accelerating innovation and discovery in medicine. The School of Medicine is the founding school of the University of Maryland and is an integral part of the 11-campus University System of Maryland. Located on the University of Maryland’s Baltimore campus, the School of Medicine works closely with the University of Maryland Medical Center and Medical System to provide a research-intensive, academic and clinically based education. With 43 academic departments, centers and institutes and a faculty of more than 3,000 physicians and research scientists plus more than $400 million in extramural funding, the School is regarded as one of the leading biomedical research institutions in the U.S. with top-tier faculty and programs in cancer, brain science, surgery and transplantation, trauma and emergency medicine, vaccine development and human genomics, among other centers of excellence. The School is not only concerned with the health of the citizens of Maryland and the nation, but also has a global presence, with research and treatment facilities in more than 35 countries around the world. http://medschool.umaryland.edu/

Learn More

• Maryland Psychiatric Research Center