Microglia: An Interface between the Loss of Neuroplasticity and Depression

Abstract

Depression has been widely accepted as a major psychiatric disease affecting nearly 350 million people worldwide. Research focus is now shifting from studying the extrinsic and social factors of depression to the underlying molecular causes. Microglial activity is shown to be associated with pathological conditions, such as psychological stress, pathological aging, and chronic infections. These are primary immune effector cells in the CNS and regulate the extensive dialogue between the nervous and the immune systems in response to different immunological, physiological, and psychological stressors. Studies have suggested that during stress and pathologies, microglia play a significant role in the disruption of neuroplasticity and have detrimental effects on neuroprotection causing neuroinflammation and exacerbation of depression. After a systematic search of literature databases, relevant articles on the microglial regulation of bidirectional neuroimmune pathways affecting neuroplasticity and leading to depression were reviewed. Although, several hypotheses have been proposed for the microglial role in the onset of depression, it is clear that all molecular pathways to depression are linked through microglia-associated neuroinflammation and hippocampal degeneration. Molecular factors such as an excess of glucocorticoids and changes in gene expression of neurotrophic factors, as well as neuro active substances secreted by gut microbiota have also been shown to affect microglial morphology and phenotype resulting in depression. This review aims to critically analyze the various molecular pathways associated with the microglial role in depression.

Keywords: cytokines; depression; glial cells; immune; microglia; neurodegeneration; neuroprotection.

Figure 1

Study inclusion flowchart. The flowchart depicts the systematic methodology for search and inclusion of relevant articles according to the PRISMA guidelines (Liberati et al., ; Moher et al., 2009).

Figure 2

Different hypotheses for depression converge together and are interconnected. As seen in the figure, microglia can cause depression through different molecular pathways. These mechanistic pathways are sometimes interrelated making the whole mechanistic link between microglial action and depression complex. Red boxes indicate “neuroinflammatory pathway,” gray boxes indicate “altered neurotrophin levels pathway,” and “impaired hippocampal neurogenesis pathway,” blue boxes indicate “altered brain tryptophan metabolism pathway,” green boxes indicate “stimulation of peripheral immune system pathway,” brown boxes indicate “psychological/chronic stress and reduced immunity pathway,” and purple boxes indicate “Inflammasome pathway.” Black boxes are part of more than one pathways. IFN, interferon; TNF, tumor necrosis factor; IL, interleukin; P2X7, two-transmembrane ATP-gated ionotropic purinoreceptor; CVD, cardiovascular disease; LPS, lipopolysaccharide; PAMPs, pathogen-associated molecular patterns; DAMPs, damage-associated molecular patterns; CNS, central nervous system; TBI, traumatic brain injury; IDO, indoleamine 2, 3-dioxygenase enzyme; KP, kynurenine pathway.

Figure 3

Mechanistic pathways of some of the pharmacological interventions available currently to treat depression. The figure depicts mechanistic pathways of some of the pharmacological drugs that are shown to reduce the depressive-like behavior. IFN, interferon; P2X7, two-transmembrane ATP-gated ionotropic purinoreceptor. Different colors depict different mechanistic pathways of the drugs in reducing the depressive-like behavior. For example, red boxes indicate reduced M1 microglial polarization, microglial apoptosis, and morphological changes, brown boxes indicate enhanced hippocampal neurogenesis, gray boxes indicate restoration of microglial morphology to resting state, blue boxes indicate reduced neuroinflammation and neurodegeneration and green boxes indicate reduced inflammasome activation.