Sex- and suicide-specific alterations in the kynurenine pathway in the anterior cingulate cortex in major depression

Abstract

Major depressive disorder (MDD) is a serious psychiatric disorder that in extreme cases can lead to suicide. Evidence suggests that alterations in the kynurenine pathway (KP) contribute to the pathology of MDD. Activation of the KP leads to the formation of neuroactive metabolites, including kynurenic acid (KYNA) and quinolinic acid (QUIN). To test for changes in the KP, postmortem anterior cingulate cortex (ACC) was obtained from the National Institute of Health NeuroBioBank. Gene expression of KP enzymes and relevant neuroinflammatory markers were investigated via RT-qPCR (Fluidigm) and KP metabolites were measured using liquid chromatography-mass spectrometry in tissue from individuals with MDD (n = 44) and matched nonpsychiatric controls (n = 36). We report increased IL6 and IL1B mRNA in MDD. Subgroup analysis found that female MDD subjects had significantly decreased KYNA and a trend decrease in the KYNA/QUIN ratio compared to female controls. In addition, MDD subjects that died by suicide had significantly decreased KYNA in comparison to controls and MDD subjects that did not die by suicide, while subjects that did not die by suicide had increased KYAT2 mRNA, which we hypothesise may protect against a decrease in KYNA. Overall, we found sex- and suicide-specific alterations in the KP in the ACC in MDD. This is the first molecular evidence in the brain of subgroup specific changes in the KP in MDD, which not only suggests that treatments aimed at upregulation of the KYNA arm in the brain may be favourable for female MDD sufferers but also might assist managing suicidal behaviour.

Fig. 1. Sex-specific alterations in the kynurenine pathway are present in major depressive disorder.

A Kynurenic acid (KYNA) was significantly decreased in females with major depressive disorder (MDD) compared to controls (p = 0.036). KYNA was significantly higher in female controls compared to male controls (p = 0.012). B The KYNA/QUIN ratio was significantly higher in female controls compared to male controls (p = 0.017). There was a trend decrease in the KYNA/QUIN ratio in females with MDD compared to female controls (p = 0.056). C KMO mRNA was significantly higher in male controls compared to female controls (p = 0.004). In females, MDD subjects had a trend increase in KMO mRNA compared to female controls (p = 0.067). D There was a main diagnostic effect for KYAT2 mRNA. KYAT2 mRNA was significantly increased in MDD compared to controls (p = 0.025). E IL1B and (F) IL6 mRNAs were significantly increased in MDD compared to controls (p = 0.017, p = 0.039, respectively). Controls are represented by circles and MDD subjects are represented by squares. Outlined shapes represent male subjects. Bars indicate mean ± SEM. *p < 0.05, **p < 0.01.

Fig. 2. Suicide-specific alterations in the kynurenine pathway.

A Kynurenic acid (KYNA) was significantly decreased in major depressive disorder subjects that died by suicide (MDD-S) compared to controls (p = 0.011) and decreased compared to MDD subjects that did not die by suicide (MDD-NS) (p = 0.045). B KYAT2 mRNA was significantly increased in MDD-NS compared to controls (p = 0.004). Female subjects are represented by darker colour. Bars indicate mean ± SEM. *p < 0.05, **p < 0.01.

Fig. 3. Quinolinic acid is positively correlated with age in major depressive disorder.

A There was no significant correlation between quinolinic acid (QUIN) and age in controls (p = 0.664). B In major depressive disorder (MDD) there was a strong positive correlation between QUIN and age (r_s = 0.575 p < 0.001). C There was no correlation between age and kynurenic acid (KYNA) in controls or (D) in MDD. Males are represented by the outlined shapes.

Fig. 4. Overview of the kynurenine pathway in the brain and key findings in MDD.

In the brain, tryptophan can be metabolised in glial cells via the kynurenine pathway. Dependent on the cell type different neuroactive metabolites will be produced. Predominantly in microglia, kynurenine is metabolised into quinolinic acid whereas kynurenic acid is primarily produced in astrocytes. In the anterior cingulate cortex, IL6, IL1B and KYAT2 mRNAs were increased in major depressive disorder (MDD) overall. KYAT2 mRNA was increased in MDD subjects that did not die by suicide in comparison to controls. Kynurenic acid was decreased in females with MDD in comparison to female controls and was decreased in MDD subjects that died by suicide in comparison to MDD-non-suicide and controls. Abbreviations: 3-HAO 3-hydroxyanthranilate 3,4-dioxygenase, ACMSD α-amino-β-carboxymuconate-ε-semialdehyde, IDO1 indoleamine 2, 3-dioxygenase, IL interleukin, KAT kynurenine aminotransferase, KMO kynurenine 3-monoxygenase, KYNU kynurinase, MDD major depressive disorder, NAD+ nicotinamide adenine dinucleotide, TDO tryptophan 2,3-dioxygenase, QPRT quinolinic acid phosphoribosyltransferase.