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.

Enforced microglial depletion and repopulation as a promising strategy for the treatment of neurological disorders

“…Apart from beneficial roles in the development of CNS, microglia can be widely involved in various types of neurological disorders, including stroke (Guruswamy & ElAli, ; Kronenberg et al, ), multiple sclerosis (MS) (Bogie, Stinissen, & Hendriks, ; Luo et al, ), AD (Hansen, Hanson, & Sheng, ; Sarlus & Heneka, ), PD (Subramaniam & Federoff, ), sleep disorders (Nadjar, Wigren, & Tremblay, ), amyotrophic lateral sclerosis (ALS) (Geloso et al, ; Liu & Wang, ), Huntington's disease (H. M. Yang, Yang, Huang, Tang, & Guo, ), epilepsy (Eyo, Murugan, & Wu, ; Zhao, Liao, et al, ), gliomas (Hambardzumyan, Gutmann, & Kettenmann, ; Schiffer, Mellai, Bovio, & Annovazzi, ), Prion diseases (Aguzzi & Zhu, ; Obst, Simon, Mancuso, & Gomez‐Nicola, ), psychiatric disorders (Mondelli, Vernon, Turkheimer, Dazzan, & Pariante, ; Prinz & Priller, ; Setiawan et al, ; Singhal & Baune, ), neuropathic pain (Inoue & Tsuda, ; Peng et al, ), adrenomyeloneuropathy (Gong et al, ), and traumatic brain injury (Donat, Scott, Gentleman, & Sastre, ). In general, microglia can be rapidly activated depending upon different stimulatory contexts and environmental changes through diverse molecular and cellular programs, subsequently transforming into the activated state and enhancing the expression of the Toll‐like receptors which sensitively bind microbial structures (Arcuri et al, ).…”

Social defeat stress: Mechanisms underlying the increase in rewarding effects of drugs of abuse

“…), which when stimulated, induce proliferation, recruitment of monocytes from the peripheral blood, release of pro‐inflammatory cytokines and expression of several cell surface antigens (e.g., Iba1; Kettenmann et al., ; Wohleb, Powell, Godbout, & Sheridan, ). The well‐known stress‐induced depression effect induced through microglial activation (Tong et al., ) is hypothesized to involve inflammation of neurons, neurodegeneration and apoptosis, impaired neurogenesis, production of stress proteins, or alteration in neurotrophin metabolisms (see Singhal and Baune, ).…”

The development and tendency of depression researches: Viewed from the microbiota-gut-brain axis

“…早期研 [56,57] . 随 后 研 究 发 现 , HPA 失 调 会 减 少 BDNF 表 达 [58] , 抑制5-HT合成 [59] , 减少Glu受体表达 [60] , 甚至 影响神经可塑性和神经环路功能 [13,61] .…”

“…高 水平的促炎症细胞因子可抑制 HPA轴负反馈功能 , 提高血脑屏障渗透性, 降低5-HT合成, 扰乱Glu能系 统, 从而引发抑郁 [59,62,66,67] . 早期理论主要集中于外 周炎症, 最新理论很多, 但都认为中枢炎症在抑郁发 生 中 发 挥 重 要 作 用 , 如 神 经 炎 症 假 说 和 炎 性 体 假 说 [61,66] . 神经炎症假说强调心理应激、疾病和感染等 各种因素引起小胶质细胞释放过量促炎症细胞因子 对中枢神经系统(central nervous system, CNS)的不利 影响 [61] , 而炎性体假说则更关注炎性体引发的中枢 炎症的影响 [68,69] .…”