Roles of microglia in adult hippocampal neurogenesis in depression and their therapeutics

Abstract

Adult hippocampal neurogenesis generates functional neurons from neural progenitor cells in the hippocampal dentate gyrus (DG) to complement and repair neurons and neural circuits, thus benefiting the treatment of depression. Increasing evidence has shown that aberrant microglial activity can disrupt the appropriate formation and development of functional properties of neurogenesis, which will play a crucial role in the occurrence and development of depression. However, the mechanisms of the crosstalk between microglia and adult hippocampal neurogenesis in depression are not yet fully understood. Therefore, in this review, we first introduce recent discoveries regarding the roles of microglia and adult hippocampal neurogenesis in the etiology of depression. Then, we systematically discuss the possible mechanisms of how microglia regulate adult hippocampal neurogenesis in depression according to recent studies, which involve toll-like receptors, microglial polarization, fractalkine-C-X3-C motif chemokine receptor 1, hypothalamic-pituitary-adrenal axis, cytokines, brain-derived neurotrophic factor, and the microbiota-gut-brain axis, etc. In addition, we summarize the promising drugs that could improve the adult hippocampal neurogenesis by regulating the microglia. These findings will help us understand the complicated pathological mechanisms of depression and shed light on the development of new treatment strategies for this disease.

Single-cell sequencing reveals an important role of SPP1 and microglial activation in age-related macular degeneration

“…Subsequently, the expression of phenotype and functional markers of microglia in AMD neuroretina was investigated. The results showed that inflammatory cytokines (including IL1B, IL6, and TNF) ( Fang et al, 2023 ), microglial phagocytic markers (CTSB, GRN, and C1QA) ( De Schepper et al, 2023 ), cell migration signatures (FAK, RAC1, and CDC42) ( Rosmus et al, 2022 ), and classic disease-associated microglia (DAM) markers (IBA1, CST3, HEXB, APOE, and TREM2) ( Deczkowska et al, 2018 ) were upregulated in microglia, while the anti-inflammatory cytokines (IL10 and TGFB) ( Fang et al, 2023 ) were at low expression levels in microglia ( Figure 5A ). Pathway enrichment analysis was then performed and the mainly upregulated pathways in microglia of AMD neuroretina included phagocytosis-related pathways (Phagosome, Microglia phagocytosis pathway, Synapse pruning, Regulation of cell killing, and Positive regulation of neuron death), complete activation-associated pathways (C1q complex and Complete activation), inflammation-related pathways (IL-18 signaling pathway and Regulation of inflammatory response) and Regulation of chemotaxis pathway ( Figure 5B ).…”

Role of Glial Cells in Depression and Drug Addiction

“…The crucial role of hippocampal BDNF in mood regulation has been amply documented [18][19][20][21][22]. Thus, it has been confirmed that dysregulation or impairment in BDNF could precipitate MDD 3 [23] [24]. Conversely, BDNF injection directly into the hippocampus imparts an antidepressant effect, and up-regulation of BDNF is often associated with an anti-depressant response [25].…”

“…At stage 4, the mature neurons establish synaptic connections via their dendrites and axons, with other neurons and glial cells, ensuring normal CNS functioning [27]. Indeed, newly born neurons in the DG of the adult brain contribute to the cognitive and emotional functions of the hippocampus [23][24] [28].…”

“…Thus, overactivation of adenosine A2A receptors (Rs), P2X7, P2Y1, and P2Y11Rs, result in neuroinflammation, disruption of the neuro-glia communication and synaptic plasticity in depression-relevant areas of the brain such as hippocampus, medial prefrontal cortex, and amygdala. Curiously, astrocytic A1Rs may impart neuroprotective and immunosuppressive effects, which could present novel intervention targets in MDD [23] [178].…”

Potential antidepressant effects of Traditional Chinese botanical drug formula Chaihu-Shugan-San and its active ingredients

“…Neuroglial cells play a significant role in the normal physiological processes of the central nervous system, including synaptic transmission, neural plasticity, regulation of neurons, and the local microenvironment ( Fang et al, 2023 ). Microglial cells are the resident immune cells of the CNS, constituting approximately 5%–10% of CNS cells in mice and 0.5%–16.6% in human CNS cells.…”