By Macquarie University
April 10, 2019
A study published in Molecular Psychiatry has identified changes in inflammation-related biochemical pathways in schizophrenia that interfere with proper brain nerve cell communication. Researchers have found the first direct evidence in support of increased kynurenic acid production in the brain, which is known to block a key glutamate receptor. This discovery paves the way for development of better targeted therapies with fewer side effects for people with schizophrenia.
The study is a collaboration between Neuroscience Research Australia (NeuRA), UNSW Sydney and Macquarie University.
The study found elevated kynurenic acid in the brains of people with schizophrenia suggesting an overproduction of kynurenic acid, especially in response to inflammation, which could be detrimental to brain function.
"We found that inflammation plays an important role in the brain pathology of schizophrenia. However, we do not know which avenue of inflammation leads to the brain pathology of schizophrenia," said Professor Cynthia Shannon Weickert, from NeuRA and UNSW Sydney.
"This is exciting for the field of schizophrenia research, because in addition to our previous findings that point to the immune cell's role in schizophrenia, we have now identified another cell target in the brain. This provides a better understanding of the molecular and cellular mechanisms underlying the deleterious effects of neuroinflammation."
It has long been suspected that metabolism of the amino acid tryptophan, commonly known to produce the "feel-good" neurotransmitter serotonin, is involved in schizophrenia. During inflammation, tryptophan is broken down into kynurenine, which can then can go down one of two avenues; one that forms a chemical compound called quinolinic acid and one called kynurenic acid. There is debate about which avenue leads to brain pathology in schizophrenia.
But now researchers have narrowed down the culprit to increased kynurenic acid production and they have other evidence to suggest that astrocytes are also involved. Astrocytes are the main cells that provide food and metabolic support to the brain nerve cells and in the case of schizophrenia, they are providing more kynurenic acid.
Kynurenic acid plays an important role protecting brain cells from overstimulation by blocking the brain's N-methyl-d-aspartate receptor (NMDAR). However, NMDAR blockade can also lead to psychosis.
"We have pinpointed the source of the problem," said Professor Gilles Guillemin, a world-renowned expert in tryptophan research from Macquarie University. "This understanding provides a new target for cell-specific treatments that reduce kynurenic acid production. What we need to find out is why people with schizophrenia have higher expression of the kynurenic acid-producing enzyme."
