- In patients with schizophrenia, higher than normal levels of kynurenic acid also known as KYNA are seen.
- Higher levels of KYNA disrupts glumate signaling and reduces its levels.
- The decreased levels of glutamate may be responsible for a number of cognitive-related symptoms of schizophrenia.
Adjusting levels of a compound called kynurenic acid can have significant effects on schizophrenia-like behavior.
The new study by researchers from the University of Maryland School of Medicine researchers has found these schizophrenia-related changes in mice.
Kynurenic acid also known as KYNA has been identified as a potential key player in schizophrenia.
KYNA is a metabolite of the amino acid tryptophan and it decreases glutamate.
Research has found that glutamate signaling in people with schizophrenia tend to be less compared to people without the disease.
The cognitive related symptoms of schizophrenia like memory and thinking can be attributed to the reduced glutamate signaling and therefore the higher KYNA levels.
Robert Schwarcz, PhD, a Professor in the Department of Psychiatry at the University of Maryland School of Medicine (UM SOM), identified the presence of KYNA in the brain in 1988.
Study in Mice
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."
Researchers examined mice that were deficient in kynurenine 3-monooxygenase, or KMO, an enzyme that is crucial for determining the levels of KYNA in the brain. Lower KMO results in higher levels of KYNA.
The mice with lower levels of KMO showed:
- impairments in contextual memory and spent less time interacting with an unfamiliar mouse in a social setting
- showed increased anxiety-like behavior when put into a maze and other challenging settings
Researchers found that patients with schizophrenia have lower than normal brain levels of KMO, which may be linked to lower levels of glutamate. This suggests that KMO and KYNA may play a key role in the disease.
The research team have demonstrated cognition in animals that have cognitive deficits similar to those seen in schizophrenia can be improved by reduction in KYNA improves
Dr. Schwarcz and his colleagues propose to indirectly modify KYNA to adjust glutamate levels as it does not trigger any side-effects. Whereas, boosting glutamate on a large scale can cause serious side effects, including seizures and nerve cell death.
SInce this mechanism is indirect, it seems not to trigger the same side effects that directly boosting glutamate does.
The study appears in the latest issue of the journal Biological Psychiatry.
- Robert Schwarcz et al. Biological Psychiatry; (2017)