Schizophrenia is a chronic, severe mental condition that affects over 1 percent of the adult population in the United States.
Although it is not yet known what causes the disease, the medical scientific community is investigating the complex neurochemical processes that may trigger this debilitating illness.
Recent studies have suggested that kynurenic acid (KYNA) plays a key role in the pathophysiology of schizophrenia. People with schizophrenia have been shown to possess higher levels of KYNA than healthy individuals.
KYNA helps to metabolize tryptophan – an essential amino acid that, in turn, helps the body to produce the “happiness” neurotransmitter serotonin, and the vitamin niacin.
Additionally, KYNA decreases glutamate – a nonessential amino acid widely recognized as the most important neurotransmitter for healthy brain functioning.
One of the most prominent hypotheses to recently emerge in the scientific community is that decreased levels of glutamate in the brain might explain the brain dysfunction in schizophrenia.
Building on this existing research, a team of scientists from the University of Maryland School of Medicine in Baltimore set out to investigate the pathological role of KYNA in mice and the connection with schizophrenia-like behavior.
The findings were published in the journal Biological Psychiatry.
KMO-deficient mice with high KYNA show schizophrenia-like symptoms
The researchers were led by Robert Schwarcz, Ph.D., a professor in the Department of Psychiatry at the University of Maryland School of Medicine.
In 1988, Prof. Schwarcz was the first to identify the role of KYNA in the brain, having studied the compound in rodents and its association with schizophrenia and other neuropsychiatric diseases.
In this new study, Prof. Schwarcz and colleagues studied the adaptive changes in genetically modified mice that had the kynurenine 3-monooxygenase enzyme (KMO) deleted.
KMO is a key factor that influences KYNA levels in the brain. When KMO levels decrease, KYNA levels increase.
Using six schizophrenia-specific behavioral assays, the scientists characterized the KMO-deficient mice. Scientists performed genome-wide analyses of the differential gene expression in the cerebral cortex and cerebellum of the rodents.
The analysis revealed increased KYNA levels in KMO-deficient mice, as expected. Researchers also found higher levels of KYNA in the cerebellum than in the cerebrum.
The cerebrum makes up most of the brain, whereas the cerebellum is a small section of the brain underneath and behind the cerebral hemispheres.
Interestingly, KMO-deficient mice displayed contextual memory problems and spent less time socializing with unfamiliar mice, compared with control mice. During the maze and light-dark box tasks, genetically modified mice also exhibited increased anxiety-like behavior.
Since increased anxiety, lack of desire to socialize, and context memory impairment are typical symptoms of schizophrenia, the present study suggests that KMO and KYNA are crucial factors in the disease.
“This study provides crucial new support for our longstanding hypothesis. It explains how the KYNA system may become dysfunctional in schizophrenia.”
Prof. Robert Schwarcz
The study also has therapeutic implications, which Schwarcz and his colleagues are working to clarify. Increasing glutamate levels can have severe side effects, such as seizures and brain cell death, so the researchers hope to alter KYNA levels in a more precise and risk-free manner.