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.

cAMP/PKA-CREB-BDNF signaling pathway in hippocampus mediates cyclooxygenase 2-induced learning/memory deficits of rats subjected to chronic unpredictable mild stress

“…However, pathological conditions lead to an excessive inflammation response that may have a detrimental impact on neuronal. A growing body of evidence supports the hypothesis that depression is also related to the inflammation [25]. COX2 is a key enzyme in inflammation, its role and the mechanisms through which it is involved in the pathophysiology of mental disorder have been confirmed in many studies.…”

Innate immunity in the postmortem brain of depressed and suicide subjects: Role of Toll-like receptors

“…Torres-Platas et al (2011) found astrocyte hypertrophy in anterior cingulate white matter of depressed suicides [also, see review by (Mechawar and Savitz, 2016)]. These studies indicate abnormal immune function in depression and suicide postmortem brain.…”

Neurobehavioral comorbidities of epilepsy: Role of inflammation

“…Depression, including epilepsy‐associated depression, is a multifactorial disease. Among many contemplated mechanisms, the role of inflammation in exacerbating or even precipitating depressive disorder has received overwhelming clinical and experimental support . Considering the critical role of inflammation in the pathophysiology of epilepsy, it is only logical to assume that inflammation may represent a causal link between the two disorders, thereby explaining the high degree of comorbidity between epilepsy and depression.…”