Decreased quinolinic acid in the hippocampus of depressive patients: evidence for local anti-inflammatory and neuroprotective responses?

Abstract

Disturbances of glutamatergic neurotransmission and mononuclear phagocyte system activation have been described uni- and bipolar depression (UD/BD). Linking the glutamate and immune hypotheses of depression, quinolinic acid (QUIN) is synthesized by activated microglia and acts as an endogenous N-methyl-D-aspartate glutamate receptor (NMDA-R) agonist with neurotoxic properties. Recently, we observed an increased microglial QUIN expression in the subgenual and supracallosal, but not in the pregenual part of the anterior cingulate cortex in postmortem brains of suicide cases with severe depression. Since several hints point to a role of the hippocampus in depression, we extended our study and addressed the question whether microglial QUIN is also changed in subregions of the hippocampus (CA1 and CA2/3 areas) in these patients. Postmortem brains of 12 acutely depressed patients (UD, n = 6; BD, n = 6) and 10 neuropsychiatric healthy age- and gender-matched control subjects were analyzed using QUIN-immunohistochemistry. Hippocampal volumes were determined in order to assess possible neurotoxic or neurodegenerative aspects. Microglial QUIN expression in the whole group of depressed patients was either comparable (left CA1, right CA2/3) or decreased (right CA1: p = 0.004, left CA2/3: p = 0.044) relative to controls. Post hoc tests showed that QUIN was reduced both in UD and BD in the right CA1 field (UD, p = 0.048; BD, p = 0.031). No loss of hippocampal volume was detected. Our data indicate that UD and BD are associated with a local reduction in QUIN-immunoreactive microglia in the hippocampus and underline the importance of the NMDA-R signaling in depressive disorders.

Reduced kynurenine pathway metabolism and cytokine expression in the prefrontal cortex of depressed individuals

“…In the anterior cingulate cortex (ACC), 1 group reported a higher density of TDO positive glial cells in depressed individuals compared with controls 29 but revealed no change in the tissue levels of several KP metabolites, 28 whereas the other investigators described subregionspecific changes in the density of QUINpositive microglial cells in depressed individuals. 30,48 The present study, which revealed a reduction rather than an increase in brain KP metabolism in depressed individuals, indicates that an etiological link between enhanced KP metabolism and de pression does not appear to exist in the absence of overt signs of inflammatory processes in the VLPFC. Taken together, these studies and ours strongly suggest that regulation of the KP in the human brain may be regionspecific and that the consequence of compensatory mechanisms between different brain regions is affected in individuals with depression.…”

Kynurenine pathway dysfunction in the pathophysiology and treatment of depression: Evidences from animal and human studies

“…A similar study identified significantly increased QUIN immunoreactivity in the prefrontal cortex of patients with MDD and bipolar depression (Steiner et al, 2011). However, in the hippocampus from patients suffering uni- and bipolar depression a reduction in QUIN-immunoreactive microglia was observed (Busse et al, 2014). This indicates that microglia might exert a toxic or neuroprotective role, depending on brain area.…”

Microglial Gene Expression Alterations in the Brains of Patients with Psychiatric Disorders

“…M1 Microglia phenotype marker iNOS mRNA and protein levels were significantly increased in the frontal cortices of bipolar disorder patients compared with controls [40]. Additionally, QUIN staining was reduced in both unipolar and bipolar disorders in the right CA1 field as well as in depressed patients in the right CA1 and left CA2/3 of the hippocampus [69].…”