Inflammation impacting brain function in schizophrenia

Inflammation has been found to play an important role in the brain pathology of schizophrenia, a discovery which will help create better therapies for patients with the disease.

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. 

This is 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, published in Molecular Psychiatry, is a collaboration between Neuroscience Research Australia (NeuRA), UNSW Sydney and Macquarie University. 

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.”

This study also demonstrated that biochemical changes in blood can reflect the changes in the brain related to schizophrenia, such as volume loss of the prefrontal cortex and attention impairment. This suggests that the kynurenine pathway may be a viable target for the development of a clinical blood biomarker to help predict brain and cognitive changes in schizophrenia.

Associate Professor Thomas Weickert, from NeuRA, further explained: “Researchers have been seeking a biomarker of schizophrenia for a long time. Our work suggests that blood kynurenine and tryptophan levels may be able to quickly and simply inform clinicians of the brain and cognitive status, which could provide a more personalised approach to treatment with new drug therapies.”

Dr Edwin Lim, from Macquarie University’s Department of Biomedical Sciences, said that while the results of this study are promising, caution needs to be exercised in treatments aimed at reducing levels of kynurenic acid in people with schizophrenia.

“Too much kynurenic acid is evidently bad for schizophrenia, but too little kynurenic acid runs the risk of exposing patients to excitotoxic-induced neurodegeneration,” said Dr Lim. “The baseline reference will need to be established in a larger population in order for biomarkers and relevant treatment regimens to be formulated.”

Top image: Professor Gilles Guillemin and Dr Edwin Lim in the Macquarie University laboratory. Image credit: Macquarie University and NeuRA.