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

Abstract

BackgroundImmune 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.MethodsMicroglial 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.ResultsDepressed 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.ConclusionsThese results add a novel link to the immune hypothesis of depression by providing evidence for an upregulation of microglial QUIN in brain regions known to be responsive to infusion of NMDA antagonists such as ketamine. Further work in this area could lead to a greater understanding of the pathophysiology of depressive disorders and pave the way for novel NMDA receptor therapies or immune-modulating strategies.

Association of Pulmonary Tuberculosis and Ethambutol With Incident Depressive Disorder

“…20 A recent study supported this immune hypothesis: levels of quinolinic acid in the subgenual anterior cingulate cortex and anterior midcingulate cortex were significantly higher in patients with acute depression than in control patients. 21 In the present study, patients receiving more than 60 DDDs of ethambutol had a higher risk of incident depressive disorder, and the relationship between ethambutol dose and incident depressive disorder was dose dependent, as indicated by analysis of patients grouped by ethambutol dose. After stratification according to age, sex, and treatment regimen, the dose-response relationship was statistically significant in patients aged 65 years or older, men, and patients taking isoniazid, rifampin, or pyrazinamide.…”

Gunn rats with glial activation in the hippocampus show prolonged immobility time in the forced swimming test and tail suspension test

“…Steiner et al. (2011) also showed an increase in the density of quinolinic acid‐immunoreactive microglia in the anterior cingulate cortex of severely depressed individuals who committed suicide compared with matched controls. Torres‐Platas et al.…”

“…In particular, several postmortem brain studies indicate that activated microglia are involved in both schizophrenia (Steiner et al., 2006) and major depression (Bayer, Busleia, Havasb, & Falkaia, 1999; Steiner et al., 2011). In accordance with, microglial activation may be a common finding in the pathogenesis of both the psychiatric diseases.…”

Effects of antidepressants and cyclooxygenase-2 inhibitor on cytokines and kynurenines in stimulated in vitro blood culture from depressed patients

“…It was found that peripheral activation of IDO was in concert with central cytokine responses (Raison et al 2010). Recently, Steiner et al reported that the neurotoxic metabolite quinolinic acid was overexpressed in certain areas of the postmortem brain tissues from those who committed suicide in an acute phase of depression (Steiner et al 2011). Those observations indicate that the peripheral and central relationship in immune activation induced impaired tryptophan metabolism, which is involved in pathophysiology of depression.…”