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.

Keywords: adult hippocampal neurogenesis; antidepressant; depression; microglia; neurogenesis.

Figure 1

Neurogenesis and its role in learning and memory, cognitive function, and emotion. (A) The area of neurogenesis is limited to the SVZ of the lateral ventricle and the SGZ of the hippocampus. (B) Radial glial stem cells in the subgranular zone produce neural stem cells (NSCs). Amplifying progenitor cells located in the subgranular zone arise from the asymmetric division of NSCs and differentiate into neuroblasts. Neuroblasts migrate into the granule cell layer to develop into immature granule neurons. Immature neurons grow into mature neurons, and their dendritic trees gradually extend to the molecular layer and axons extend to the CA3 subfields. (C) Under normal conditions, the axons of new granule neurons located in the DG area will extend to the CA3 and CA2 subfields to establish synaptic contacts with pyramidal neurons and integrate the pre-existing circuits, playing an important role in behaviors associated with the hippocampus. Rodents with normal neurogenesis have typical responses in some emotional tests (such as OFT, EPM, SPT, TST, and FST) and cognitive tests (such as MWM and Barnes maze). (D) In some neuropsychiatric diseases, hippocampal neurogenesis is impaired, manifested by decreased newborn neurons and impaired synaptic connections with pyramidal neurons in the CA3 and CA2 subfields. Compared to normal rodents, rodents with impaired neurogenesis exhibit anxiety-like behaviors (such as reduced entry times and residence times in the central zone in the OFT; reduced the number and frequency of exploring the open arm, and prefer to stay in the closed arm in the EPM) or depression-like behaviors on certain mood tests (such as inactive behaviors in the FST and TST; anhedonia in SPT), and impaired social cognition on some cognitive tests (such as unable to locate the location of the hidden platform in the MWM and the location of the markers in the Barnes maze). SVZ subventricular zone, SGZ subgranular zone, DG dentate gyrus, OFT open field test, EPM Elevated Plus Maze, SPT Sucrose Preference Test, TST Tail Suspension Test, FST Forced Swimming Test, MWM Morris Water Maze.

Figure 2

Microglial activation and their roles in depression. Ramified microglia stimulated by PAMPs or DAMPs are activated into three main microglial morphotypes, including hyper-ramified, activated, and amoeboid types. Alternatively, two main polarization states are defined in activated microglia: M1 and M2 phenotypes. The classic M1 polarization microglia is usually marked with iNOS, CD86, CD16 and MHC‐II. Under the M1 state, exposure to LPS and/or IFN‐γ stimulates and binds to TLR-4 or IFN‐γ receptors, respectively, leading to the activation of NF‐κB and STAT1. Meanwhile, the increase in iNOS produces a burst of ROS and RNS. All these lead to the excessive release of pro-inflammatory cytokines, such as TNF-α, IL-1β, IL-6, IL-12, and chemokines, such as CXCL9, CXCL10, CCL2, and ROS, which produce neurotoxic effects on the neurons in CNS. The alternative M2 polarization microglia is usually marked with ARG-1, CD206 and CD163. M2 microglia can also be divided into three subtypes including M2a, M2b and M2c, because of the different stimulis. Upon stimulation with IL‐4/IL‐13, the cells transform into the M2a-phenotype microglia with an increase in IL-10, CCL17 and CCL18. Exposed to TLR ligands and immune complexes, the cells transform into the M2b-phenotype microglia with an expression of IL-6. Upon stimulation with IL-10, the cells transform into the M2c-phenotype microglia with an increase in IL-4, TGF-β and CCL16. The phenotypes of M1 microglia perform functions that aberrant phagocytosis of synapses leading to produce neurotoxic effects on the neurons in CNS. The phenotypes of M2 microglia perform functions that neurotrophic support leading to produce neuroprotective effects on the neurons in CNS. Thus, the imbalance of M1 and M2 polarization induces increased excessive neurotoxicity and decreased neuroprotection, leading to depression. PAMPs pathogen-associated molecular patterns, DAMPs danger-associated molecular patterns, iNOS inducible nitric oxide synthase, CD86 cluster of differentiation 86, CD16 cluster of differentiation 16, MHC‐II major histocompatibility complex II, LPS lipopolysaccharide, IFN‐γ interferon gamma, TLR-4 toll-like receptor 4, NF‐κB transcription factors nuclear factor kappa-B, STAT1 signal transducer and activator of transcription 1, ROS reactive oxygen species, RNS reactive nitrogen species, TNF-α tumor necrosis factor α, IL-1β Interleukin-1β, Interleukin-6 IL-6, Interleukin-12 IL-12, CXCL9 chemokine (C-X-C motif) ligand 9, CXCL10 chemokine (C-X-C motif) ligand 10, CCL2 chemokines chemoattractant cytokine ligand 2, CNS central nervous system, ARG-1 arginase-1, CD206 cluster of differentiation 206, CD163 cluster of differentiation 163, IL‐4 interleukin-4, IL‐13 interleukin-13, IL-10 interleukin-10, CCL17 chemoattractant cytokine ligand 17, CCL18 chemoattractant cytokine ligand 18, IL-1 interleukin-1, Interleukin-10, IL-10 Interleukin-4 IL-4, TGF-β transforming growth factor-β, CCL16 chemoattractant cytokine ligand 16.

Figure 3

Modulation of adult neurogenesis by microglia in depressive. In a healthy central nervous system, microglia produce neurotrophic factors, phagocyte redundant neurons, and connections, remove cell debris, and control stem cell proliferation, in this way regulating synaptogenesis and neuronal pruning. In a pathological state, exogenous and endogenous factors such as infections(LPS), stress, and systemic inflammation/metabolic deregulation can induce microglial activation and impaired neurogenesis. (A) Cytokines such as IL-1β, IL-6, and TNF-α, with negative consequences to the HPA axis. (B) CX3CR1 is involved in interactions between microglia and neurons, which may reduce to pro-inflammation cytokine. (C) Inflammatory microglia(M1) also exhibit upregulated IDO, reducing serotonin availability and possibly contributing to neurogenesis in depression. (D) SCFAs、other bacterial metabolites and components of the immune system can affect microglial maturation, activation and function. (E) A neuroprotective microglial phenotype (classically referred to as “M2-like”) activated the BDNF-TrkB-CREB signaling pathway, enhanced neurogenesis, diminished synapse loss in the hippocampus, and contribute to an overall lower level of neuroinflammation. (F–H) Intracellularly, several pathways become activated including the TLR, JAK, and STAT, which will trigger the activation of the NF-κB, downregulate NLRP3, and consequent induction of first-line cytokine production, such as IL-1β, IL-6, and TNF-α. (I) MicroRNAs have been associated with multiple pathways of depression pathophysiology. LPS lipopolysaccharide, TLR toll-like receptor, JAK Janus kinase, STAT signal transducer and activator of transcription, NF-κB nuclear transcription factor-kappa B, NLRP3 nod-like receptor protein 3, IL-1β interleukin-1β, IL-6 interleukin 6, TNF-α tumor necrosis factor-alpha, HPA hypothalamic-pituitary-adrenal, IDO indoleamine 2,3-dioxygenase, CX3CR1 C-X3-C motif chemokine receptor 1, BDNF- TrkB-CREB brain derived neurotrophic factor- tyrosine kinase receptor B- cyclic adenosine monophosphate response element binding protein, SCFAs short chain fatty acids.