Severe depression is associated with increased microglial quinolinic acid in subregions of the anterior cingulate gyrus: evidence for an immune-modulated glutamatergic neurotransmission? - PubMed (original) (raw)

doi: 10.1186/1742-2094-8-94.

Martin Walter, Tomasz Gos, Gilles J Guillemin, Hans-Gert Bernstein, Zoltán Sarnyai, Christian Mawrin, Ralf Brisch, Hendrik Bielau, Louise Meyer zu Schwabedissen, Bernhard Bogerts, Aye-Mu Myint

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

Johann Steiner et al. J Neuroinflammation. 2011.

Erratum in

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.

Conclusions: These 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.

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Figures

Figure 1

Figure 1

modified from [13]: Tryptophan is an essential amino acid and a precursor for the synthesis of serotonin. Alternatively, tryptophan can be metabolized in glial cells via the kynurenine pathway to create kynurenic acid (synthesized by kynurenine aminotransferase, KAT) or quinolinic acid (QUIN). These substances are endogenous modulators of NMDA glutamate receptors. A key enzyme of the kynurenine pathway, indoleamine 2,3-dioxygenase (IDO), and the enzyme that catalyses the production of 3-OH-kynurenine, kynurenine monoxygenase (KMO), are activated by proinflammatory cytokines, including interleukin-1 and -6 (IL-1, IL-6), tumor necrosis factor a (TNFa), or interferon g (IFNg). These enzymes are inhibited by anti-inflammatory cytokines, including IL-4. Serotonin is normally broken down into 5-hydroxyindoleacetic acid (5-HIAA), but the indole ring of serotonin can also be cleaved by IDO to form formyl-5-hydroxykynurenamine (f-5-KYM). Annotation: grey arrows: activation; dotted grey lines with bar at the end: inhibition; black font: potentially neurotoxic; purple font: neutral or not known; bright blue: potentially neuroprotective.

Figure 2

Figure 2

Illustrations of QUIN-immunoreactive cells from the left sACC of a depressed suicidal patient and a control case and the locations of the analyzed regions of interest (sACC, aMCC and pACC). Depressed patients showed microglial formations with numerous granular structure processes. Annotation: Scale bars represent 20 μm.

Figure 3

Figure 3

Illustration of QUIN-immunopositive cell densities. a) Depressed patients had increased QUIN-immunopositive cell densities in the sACC and the aMCC but not in the pACC. b) MDD patients showed the highest QUIN-immunoreactive cell counts in the sACC and the aMCC compared to BD and control cases. No diagnostic subgroup-dependent differences were observed in the pACC. Annotation: The box plots show the median, interquartile range, sample minimum and sample maximum, * P < 0.05, ** P < 0.01.

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References

    1. Dantzer R, O'Connor JC, Freund GG, Johnson RW, Kelley KW. From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci. 2008;9:46–56. doi: 10.1038/nrn2297. - DOI - PMC - PubMed
    1. Drexhage RC, Knijff EM, Padmos RC, Heul-Nieuwenhuijzen L, Beumer W, Versnel MA, Drexhage HA. The mononuclear phagocyte system and its cytokine inflammatory networks in schizophrenia and bipolar disorder. Expert Rev Neurother. 2010;10:59–76. doi: 10.1586/ern.09.144. - DOI - PubMed
    1. Myint AM, Leonard BE, Steinbusch HW, Kim YK. Th1, Th2, and Th3 cytokine alterations in major depression. J Affect Disord. 2005;88:167–173. doi: 10.1016/j.jad.2005.07.008. - DOI - PubMed
    1. Kaestner F, Hettich M, Peters M, Sibrowski W, Hetzel G, Ponath G, Arolt V, Cassens U, Rothermundt M. Different activation patterns of proinflammatory cytokines in melancholic and non-melancholic major depression are associated with HPA axis activity. J Affect Disord. 2005;87:305–311. doi: 10.1016/j.jad.2005.03.012. - DOI - PubMed
    1. Miller AH, Maletic V, Raison CL. Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol Psychiatry. 2009;65:732–741. doi: 10.1016/j.biopsych.2008.11.029. - DOI - PMC - PubMed

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