TABLE 1.
Summary of recent findings on microglia function in neuroplasticity and neuro-inflammation in the hippocampus, with focus on serotonin and antidepressant action.
| Microglia in neuroplasticity and neuroinflammation | ||
| Kettenmann et al., 2011; Grabert et al., 2016 | Microglia represent a diverse and vigilant phenotype with high numbers in the dentate gyrus | |
| Pocock and Kettenmann, 2007; Szepesi et al., 2018 | 5-HT, 5-HTR | Microglia interact with local neurotransmitters and hormones |
| Gemma and Bachstetter, 2013 | Microglia contribute to adult neurogenesis | |
| Pascual et al., 2012 | TNF-α, ATP, glutamate | Synapse plasticity via microglial release of TNF-α and ATP triggering nearby astrocytes to release glutamate |
| Trang et al., 2011 | ATP, BDNF | ATP-P2X4 drives BDNF release from microglia |
| Parkhurst et al., 2013 | BDNF | Microglia-mediated synaptogenesis via BDNF |
| Ferrini and De Koninck, 2013 | BDNF | In neuroinflammation, microglia-mediated BDNF signaling causes synaptic disinhibition |
| Sierra et al., 2010; Diaz-Aparicio et al., 2020 | Microglia phagocytosis of apoptotic newborn cells in the dentate gyrus through the phagocytosis secretome | |
| Klempin et al., 2013 | Tph2, Iba-1 | Running-induced microgliosis in wild-type hippocampus that is further enhanced in mice lacking brain serotonin |
| Wasinski et al., 2018 | B2R, Iba-1 | Running-induced microgliosis in hippocampus of bradykinin B2 receptor knockout mice |
| Ehninger and Kempermann, 2003; Ehninger et al., 2011 | Iba-1 | Physical exercise increases newborn microglia numbers in cortex, but decreases the amount in adult amygdala |
| Ali et al., 2019 | Iba-1 | Long-term ENR enhances microgliosis in adult hippocampus and amygdala, hypertrophied and ramified microglia morphology |
| de Sousa et al., 2015; de Oliveira et al., 2020 | Iba-1 | Increased microglia complexity in CA3, reduced diversity in molecular layer in ENR |
| Johnson et al., 2003; Szuhany et al., 2015 | BDNF | Physical exercise strongly induces BDNF release in rodents, and humans |
| Moon et al., 2016 | BDNF | Skeletal muscle releases cathepsin B during running in monkeys that affects BDNF levels in the brain |
| Tuchina et al., 2018 | Interplay of the endocrine, immune and limbic systems during stress | |
| Goronzy and Weyand, 2013 | Senescent myeloid cells decrease process motility and chemotaxis | |
| Pickering and O’Connor, 2007 | TNF-α, IL-1, IL-18 in AD | Enhanced release of pro-inflammatory cytokines in disease progression |
| Shen et al., 2018 | AD | Dysfunctional microglia in disease progression |
| Ng et al., 2018 | IL-1β, IL-6 in AD, major depression | Enhanced peripheral levels in patients |
| Burbach et al., 2004 | BDNF in AD | In AD inflammation, release of BDNF by microglia in close proximity to plaques |
| Floden et al., 2005 | TNF-α, glutamate in AD | b-amyloid-induced microglia-mediated cell death via the release of TNF-α and glutamate |
| Makar et al., 2009 | BDNF, IL-10 | BDNF promotes IL-10 release in multiple sclerosis |
| Borsini et al., 2015 | Cytokines | Distinctive cytokines acting on cell proliferation and differentiation in vitro |
| Kelly et al., 2001; Lim et al., 2013 | IL-10 | Anti-inflammatory; promotes synaptic plasticity and long-term potentiation |
| Cacci et al., 2008; Willis et al., 2020 | IL-10 IL-6 | Potent suppression of pro-inflammation and robust support of adult neurogenesis |
| Paolicelli et al., 2011; Sellner et al., 2016; Bolós et al., 2018 | Fractalkine/CX3CR1 Cx3cr1 | Prominent chemokine regulator of neuron–microglia communication in the postnatal and adult dentate gyrus; important for synaptic pruning |
| Bachstetter et al., 2015; Milior et al., 2016 | Fractalkine/CX3CR1 in AD, chronic stress | Deficiency results in microglia-induced pro-inflammation and impaired neurogenesis |
| Monje et al., 2003; Bastos et al., 2008; Fujioka and Akema, 2010 | LPS, BrdU and neuronal markers | Dose- and time-dependent effects on cell proliferation, survival and neuronal fate in the adult dentate gyrus, in vivo/in vitro |
| Ekdahl et al., 2003 | LPS, BrdU | Negative correlation of activated microglia-newborn cells |
| Mizoguchi et al., 2014 Zhang et al., 2014 Wu et al., 2020 | LPS BDNF-TrkB | (LPS-induced) microglia activation, transformation can be reduced by BDNF or TrkB agonist treatment; BDNF sustains Ca2+ elevation |
| Serotonin–Microglia function | ||
| Stagaard et al., 1987; Vetreno et al., 2017 | 5-HT, Tph2, VMAT, SERT, Iba-1, CD11b | Serotonin depletion increases microgliosis in dorsal raphe, and subcommissural organ |
| Krishna et al., 2016 | LPS, 5-HT | Transient increased microglia numbers and a depressive-like phenotype upon chronic LPS |
| Carabelli et al., 2020 | LPS, Omega-3, 5-HT | Fish oil reverses depression-like behavior, increases serotonin in the hippocampus |
| Albertini et al., 2020 | 5-HT | Microglial processes in close proximity to serotonergic axons in the adult hippocampus |
| Seifert et al., 2011 | 5-HT, Ca2+ | Transient enhanced Ca2+ signaling in response to serotonin in vitro |
| Glebov et al., 2015 | 5-HT2A/B, 5-HT4, Ca2+ | Serotonin stimulates secretion of exosomes from microglia cells |
| Krabbe et al., 2012; Etienne et al., 2019 | 5-HTR, 5-HT2B, LPS, TNF-α, IL-6 | Serotonin promotes microglia-induced targeted motility, but attenuates phagocytosis activity |
| Kolodziejczak et al., 2015 | 5-HT2B | Serotonin–microglia neurotransmission in development |
| Béchade et al., 2021 | 5-ht2b | In the lack of 5-ht2b, overexpression of cytokines and prolonged neuroinflammation |
| de las Casas-Engel et al., 2013 | 5-HT7 | Microglia-mediated serotonin neurotransmission to maintaining anti-inflammatory state |
| Mahé et al., 2005; Wixey et al., 2018 | 5-HT7 | Present on human microglial MC-3 cells |
| Quintero-Villegas and Valdés-Ferrer, 2019 | 5-HT7, IL-6, AD | Promotes synaptogenesis and inflammatory priming via IL-6 |
| Lim et al., 2009 | FLX | Diminished microglia activation in ischemia |
| Liu et al., 2011 | FLX, TNF-α, IL-6 | Reduction in TNF-α and IL-6 secretion, in vitro |
| Jin et al., 2009 | FLX, TNF-α, IL-1β | Fluoxetine-induced neuroprotection in the dentate gyrus following kainate-mediated neuronal cell death |
| Dhami et al., 2013 | FLX, TNF-α, IL-1β | Reduction in the release of pro-inflammatory cytokines, and glutamate, in vitro |
| Alboni et al., 2016 | FLX, TNF-α, IL-1β Iba-1, CD11b | Treatment on microglia activation and cytokine release differs depending on environmental conditions |
| MacGillivray et al., 2011 | FLX, SERT, CD11b | Inhibition of SERT increases CD11b expression accompanied by loss of dopaminergic neurons |
| Zimniak et al., 2020 | FLX | Attenuates symptoms in COVID-19 patients |
5-HT, 5-hydroxytryptamine; AD, Alzheimer’s disease; ATP, adenosine triphosphate; B2R, bradykinin receptor 2; BDNF, brain-derived neurotrophic factor and its receptor TrkB (tropomyosin-related kinase receptor B); BrdU, bromodeoxyuridine (cell proliferation marker), microglia marker CD11b Integrin αM, and Iba-1 (Ionized calcium binding adaptor molecule 1); ENR, enriched environment; FLX, fluoxetine; Interleukins, IL-1 to IL-18; LPS, lipopolysaccharide; SERT, serotonin transporter; TNF-α, tumor necrosis factor; Tph2, tryptophan hydroxylase 2; VMAT, vesicular monoamine transporter.