Severe depression is associated with increased microglial quinolinic acid in subregions of the anterior cingulate gyrus: Evidence for an immune-modulated glutamatergic neurotransmission?

Abstract

Background: Immune dysfunction, including monocytosis and increased blood levels of interleukin-1, interleukin-6 and tumour necrosis factor α has been observed during acute episodes of major depression. These peripheral immune processes may be accompanied by microglial activation in subregions of the anterior cingulate cortex where depression-associated alterations of glutamatergic neurotransmission have been described. Methods: Microglial immunoreactivity of the N-methyl-D-aspartate (NMDA) glutamate receptor agonist quinolinic acid (QUIN) in the subgenual anterior cingulate cortex (sACC), anterior midcingulate cortex (aMCC) and pregenual anterior cingulate cortex (pACC) of 12 acutely depressed suicidal patients (major depressive disorder/MDD, n = 7; bipolar disorder/BD, n = 5) was analyzed using immunohistochemistry and compared with its expression in 10 healthy control subjects. Results: Depressed patients had a significantly increased density of QUIN-positive cells in the sACC (P = 0.003) and the aMCC (P = 0.015) compared to controls. In contrast, counts of QUIN-positive cells in the pACC did not differ between the groups (P = 0.558). Post-hoc tests showed that significant findings were attributed to MDD and were absent in BD.

Putative Neuroprotective and Neurotoxic Kynurenine Pathway Metabolites Are Associated with Hippocampal and Amygdalar Volumes in Subjects with Major Depressive Disorder

“…IL-1 was shown not only to decrease hippocampal neurogenesis in human hippocampal progenitor cells but also to upregulate the expression of the enzymes, IDO, KMO, and kynureninase and, crucially, treatment with a KMO inhibitor reversed the effects of IL-1 on hippocampal neurogenesis (Zunszain et al, 2012). The reduction in GM volume and the decrease in neuronal density that has been found in some depressed patients post-mortem may be related to higher brain concentrations of microglia-derived QA, as was recently reported in subjects with MDD (Steiner et al, 2008(Steiner et al, , 2011. Conversely, psychiatric medication may increase the synthesis of the potentially neuroprotective compound, KA, and/or decrease the synthesis of 3HK.…”

Mouse chronic social stress increases blood and brain kynurenine pathway activity and fear behaviour: Both effects are reversed by inhibition of indoleamine 2,3-dioxygenase

“…For example, relative to healthy controls, MDD patients have increased blood KYN (Bay-Richter et al, 2015;Kim et al, 2012;Sublette et al, 2011), and the density of QUIN-positive microglia was increased in anterior cingulate cortex in MDD patients (Steiner et al, 2011) (for review: (Reus et al, 2015)). …”

“…KYN is further metabolized to, among others, 3-hydroxykynurenine (3-HK), quinolinic acid (QUIN) and kynurenic acid (KYNA), catabolites that can contribute to oxidative stress, excitotoxicity, and neuroprotection (for review: (Chiarugi et al, 2001;Haroon et al, 2012;Schwarcz et al, 2012). There is growing evidence for kynureninepathway hyperfunction in stress-related disorders, particularly for MDD (Bay-Richter et al, 2015;Kim et al, 2012;Reus et al, 2015;Savitz et al, 2015;Steiner et al, 2011;Sublette et al, 2011) (for review: (Maes et al, 2011)). …”

Therapeutic Implications of Brain–Immune Interactions: Treatment in Translation

“…Although much of the attention of the literature has been focused on immunologic parameters in the peripheral blood, it should be noted that although the literature is not entirely consistent (Clark et al, 2016), increased activation of microglial cells as well as increased expression of inflammatory cytokines and Toll-like receptors have been described in postmortem brain samples of presumably depressed suicide victims (Steiner et al, 2008(Steiner et al, , 2011Pandey et al, 2012Pandey et al, , 2014Torres-Platas et al, 2014). Inconsistencies in the literature have been attributed to diagnostic considerations, use of medications, brain regions sampled, and small sample sizes.…”

“…In addition, inflammatory cytokine-induced activation of IDO can lead to the production of quinolinic acid by microglia that can bind to glutamate (N-methyl-Daspartate (NMDA)) receptors while also stimulating glutamate release from astrocytes (Tavares et al, 2002(Tavares et al, , 2005Schwarcz et al, 2012). Indeed, in studies from postmortem tissue of presumably depressed suicide victims, activated microglia expressing quinolinic acid have been described in the anterior cingulate cortex (Steiner et al, 2011). Interestingly, studies in laboratory animals administered LPS have shown that pretreatment with the glutamate antagonist ketamine can reverse LPS-induced depressive-like behavior while having no effect on LPS-induced inflammation in the brain (Walker et al, 2013).…”