Oligodendrocyte lineage cells and depression

Abstract

Depression is a common mental illness, affecting more than 300 million people worldwide. Decades of investigation have yielded symptomatic therapies for this disabling condition but have not led to a consensus about its pathogenesis. There are data to support several different theories of causation, including the monoamine hypothesis, hypothalamic-pituitary-adrenal axis changes, inflammation and immune system alterations, abnormalities of neurogenesis and a conducive environmental milieu. Research in these areas and others has greatly advanced the current understanding of depression; however, there are other, less widely known theories of pathogenesis. Oligodendrocyte lineage cells, including oligodendrocyte progenitor cells and mature oligodendrocytes, have numerous important functions, which include forming myelin sheaths that enwrap central nervous system axons, supporting axons metabolically, and mediating certain forms of neuroplasticity. These specialized glial cells have been implicated in psychiatric disorders such as depression. In this review, we summarize recent findings that shed light on how oligodendrocyte lineage cells might participate in the pathogenesis of depression, and we discuss new approaches for targeting these cells as a novel strategy to treat depression.

Fig. 1. Differentiation and proliferation of oligodendrocyte lineage cells.

Based on the expression of different special proteins, the origin and development of oligodendrocyte lineage cells can be subdivided into three stages: oligodendrocyte progenitor cells (OPCs), premyelinating oligodendrocytes and mature oligodendrocytes (OLs). Originating from neural stem cells, OL lineage cells begin to express PDGFRα, NG2 (OPCs), galactocerebroside, Oligo2 (premyelinating OLs) and, finally, mature myelin antigens such as MBP and PLP (proteolipid protein). The purple and yellow dashed lines indicate the diverse differentiation potential of OPCs, although this signaling pathway is still under debate.

Fig. 2. An overview of the functional roles of oligodendrocyte lineage cells in depression.

Under extreme social pressure, glutamate, ATP, 5-HT or the adrenal cortical hormone released by the activated hypothalamic–pituitary–adrenal axis stimulates different signaling pathways in oligodendrocyte lineage cells. These signaling pathways may affect myelin gene transcription, myelin-associated genes to cause demyelination or increase [Ca²⁺]_i to a toxic level. Moreover, some molecular factors released by oligodendrocyte lineage cells, such as microRNAs, Neuregulin 1, fibroblast growth factor 2 (FGF2), γ-secretase or GABA, also influence the homeostasis of the central nervous system. Under the stimulation of stress, inflammatory factors released by oligodendrocyte lineage cells can directly affect the immune system and cause depression.