Kynurenic acid observed to indirectly raise glutamate levels.
A new study published by Biological Psychiatry shows that altering levels of kynurenic acid (KYNA) can improve schizophrenia-like behavior in mice.
In previous studies, the authors discovered a link between KYNA and the condition. Patients with schizophrenia are known to have higher levels of KYNA, a metabolite of the tryptophan amino acid that decreases glutamate. Patients with schizophrenia typically have reduced glutamate signaling, which makes KYNA a potential treatment target.
The authors also speculated that reduced glutamate activity leads to higher KYNA levels, and leads to schizophrenia-like symptoms.
In the new study, the research team collaborated with scientists at the Karolinska Institute, the University of Leicester, and biotech company KynuRex to further explore the relationship between KYNA and schizophrenia.
"This study provides crucial new support for our longstanding hypothesis," said Robert Schwarcz, PhD. "It explains how the KYNA system may become dysfunctional in schizophrenia."
Dr Schwarcz was the first to identify KYNA’s presence in the brain, and has studied its role in schizophrenia and other neuropsychiatric diseases, according to a press release.
In the current study, the team examined mice that were deficient in kynurenine 3-monooxygenase (KMO). This enzyme is critical for determining KYNA levels in the brain, with low levels of KMO resulting in higher levels of KYNA, according to the study.
Patients with schizophrenia have been observed to have lower levels of KMO, which may lead to lower glutamate levels.
The investigators found that mice with low levels of KMO had impaired contextual memory. These mice also spent less time interacting with an unfamiliar mouse in a social setting, compared with the control group, according to the study.
Mice with low levels of KMO were also observed to have high anxiety-like behavior when inside of a maze or in other challenging settings.
Since these behaviors are similar to schizophrenia symptoms in human patients, the findings suggest that KMO and KYNA may be involved with the disease, according to the study.
The new findings also have implications for new schizophrenia treatments. Increasing glutamate levels directly comes with serious side effects, such as seizures or nerve cell death. The investigations said that modifying KYNA could increase glutamate levels more effectively without side effects.
The team also found that reduced KYNA improves cognition in animal models with schizophrenia-like symptoms. Since the mechanism is indirect, it does not elicit the same negative effects as increasing glutamate levels directly.
The investigators are now working to create compounds that elicit the same effects in humans, the study concluded.