Neuropathology of mood disorders: do we see the stigmata of inflammation?

Abstract

A proportion of cases with mood disorders have elevated inflammatory markers in the blood that conceivably may result from stress, infection and/or autoimmunity. However, it is not yet clear whether depression is a neuroinflammatory disease. Multiple histopathological and molecular abnormalities have been found postmortem but the etiology of these abnormalities is unknown. Here, we take an immunological perspective of this literature. Increases in activated microglia or perivascular macrophages in suicide victims have been reported in the parenchyma. In contrast, astrocytic markers generally are downregulated in mood disorders. Impairment of astrocytic function likely compromises the reuptake of glutamate potentially leading to excitotoxicity. Inflammatory cytokines and microglia/macrophage-derived quinolinic acid (QA) downregulate the excitatory amino acid transporters responsible for this reuptake, while QA has the additional effect of inhibiting astroglial glutamine synthetase, which converts glutamate to glutamine. Given that oligodendroglia are particularly vulnerable to inflammation, it is noteworthy that reductions in numbers or density of oligodendrocyte cells are one of the most prominent findings in depression. Structural and/or functional changes to GABAergic interneurons also are salient in postmortem brain samples, and may conceivably be related to early inflammatory insults. Although the postmortem data are consistent with a neuroimmune etiology in a subgroup of depressed individuals, we do not argue that all depression-associated abnormalities are reflective of a neuroinflammatory process or even that all immunological activity in the brain is deleterious. Rather, we highlight the pervasive role of immune signaling pathways in brain function and provide an alternative perspective on the current postmortem literature.

Figure 1

Main branches of the kynurenine pathway. The enzyme indoleamine 2,3 deoxygenase (IDO), which converts tryptophan to kynurenine is upregulated by pro-inflammatory cytokines. Each box represents a metabolite resulting from the oxidation of tryptophan. The black italicized text shows the enzymes that catalyze select steps in the metabolic pathway. NMDA, N-methyl-d-aspartate.

Figure 2

(Torres-Platas et al.): Four main IBA1-IR microglial phenotypes are observed in human dorsal anterior cingulate cortex (ACC). Representative examples are illustrated here for the white matter. (a) Ramified microglial cell body and highly ramified processes. (b) Primed microglia display a wider cell body compared with the ramified phenotype. (c) Reactive microglia present an ameboid-shaped rounder cell body with a few ramified processes, whereas (d) ameboid microglia display a characteristic ameboid-shaped cell body extending one or two unramified processes (top panel) or are completely devoid of processes (bottom panel). Scale bars, 10 μm. IR, immunoreactive.

Figure 3

Golgi-stained astrocytes in the human dorsal anterior cingulate cortex (dACC). These cells extend tortuous varicose and thorny processes radiating in all the directions and often are observed to contact adjacent blood vessels, which are also silver-impregnated.

Figure 4

Representative micrographs of immunostained oligodendrocyte precursor cells (PDGFRα- and NG2-immunoreactive), oligodendrocyte-lineage cells (Olig2-immunoreactive) and mature oligodendrocytes (Nogo-A-immunoreactive) in ventromedial prefrontal cortex white matter at low (left column) and high (right column) magnifications. Note the characteristic distribution of Nogo-A+ mature oligodendrocytes along axonal fibers.