「ミクログリアまつり」シンポジウム２
"Microglia Matsuri" Symposium 2 |
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| 2020/9/12 10:50～11:15 Zoom A
MM2-01
生体イメージングで明らかにするミクログリアの生理機能および病態の寄与
Illuminate the physiological and pathological function of microglia
*和氣 弘明1
1. 名古屋大学大学院医学系研究科 分子細胞学
*Hiroaki Wake1
1. Department of Anatomy and Molecular Cell Biology, Nagoya University Graduate School of Medicine
Microglia are the sole immune responding cells in the central nervous system. Their role as neuro-immune cells in the pathogenesis of various neurodegenerative and infectious diseases of the brain have been extensively studied. Upon brain disease and infection, the adopt an activated phenotype associated with the release of cytokines and neurotrophic factors and resulting in neuroprotective or neurotoxic outcomes. However, microglia are resident also in the healthy or physiological brain, but much less is known about their role(s) in the healthy brain, partly due to technical limitations involved with investigate these highly reactive cells in the intact brain. Recent developments in molecular probes and optical imaging in vivo has now helped to characterize microglia in the physiological or healthy brain. In vivo two-photon imaging of fluorescently labelled microglia have revealed they are highly motile cell in the healthy brain, extending and retracting their process that extend from a largely stationary cell soma. We used in vivo two photon microscope to reveal their physiological and pathological function on synapse and vessels. We particularly showed the functional consequence of microglial contact on synapse and vessels to indicate their role in neurological or psychiatric brain.
| | 2020/9/12 11:15～11:40 Zoom A
MM2-02
胎生期大脳におけるミクログリア分布の時空間的制御とその生理学的意義
Spatiotemporal control of microglial distribution in the developing cerebral cortex and its biological significance
*服部 祐季1
1. 名古屋大学大学院医学系研究科 細胞生物学分野
*Yuki Hattori1
1. Department of Anatomy and Cell Biology, Graduate School of Medicine, Nagoya University
Microglia have been reported to play multiple roles in neurogenesis in the embryonic brain, e.g., by phagocytotically regulating the number of neural progenitors and inducing neural stem-like cells to differentiate into intermediate progenitors. Although microglia account for only a minor population of the cells that constitute the embryonic cerebral cortex, they extensively survey the entire structure and are thus capable of providing the particular functions that are required in specific regions. Of note, such actively moving microglia exhibit mysterious behavior in the midembryonic cerebral wall. In mice, intrapallial microglial distribution is initially homogenous until embryonic day (E) 14, but these cells temporarily disappear from the cortical plate (CP) from E15 to E16 and show preferences for colonizing the ventricular zone, subventricular zone (SVZ), and intermediate zone. However, the mechanism and significance of this absence are unknown.
We demonstrated that microglia bidirectionally migrate via attraction by CXCL12 released from the meninges and SVZ, and thereby exit the midembryonic CP. Upon nonphysiological excessive exposure to microglia in vivo or in vitro, young postmigratory and in vitro-prepared CP-composing neurons showed abnormal differentiation with disturbed expression of the subtype-associated transcription factors and genes implicated in functional neuronal maturation. Notably, this effect is primarily attributed to interleukin 6 and type I interferon secreted by microglia. These results suggest that "sanctuarization" from microglia in the midembryonic CP is required for neurons to appropriately fine-tune the expression of molecules needed for proper differentiation, thus securing the establishment of functional cortical circuit.
| | 2020/9/12 11:40～12:05 Zoom A
MM2-03
ミクログリア動態の可視化によるシナプス貪食の分子メカニズム解明
Visualizing microglial dynamics to unveil molecular mechanisms underlying synapse engulfment
*小山 隆太1
1. 東京大学大学院薬学系研究科 薬品作用学教室
*Ryuta Koyama1
1. Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Science, The University of Tokyo
Microglial engulfment of pre- and post-synaptic elements has been confirmed both in health and disease by microscopy in fixed tissue, while phagocytic cups containing synaptic elements were observed in vivo; however, direct real-time evidence is lacking on how microglia engulf synapses from living neurons. To answer the question, we have developed a novel in vitro system of neuron-glia cocultures in which an in vitro issue of abnormal microglial morphology is overcame and microglia maintain highly ramified processes. Using the in vitro system, we examined how synaptic engulfment is controlled when the well-recognized “eat-me” signal, complement C1q, ubiquitously exists in the extracellular milieu, because C1q sometimes, especially in disease, seems ubiquitously spread in the brain parenchyma which may result in uncontrolled synaptic elimination. Live-imaging analysis revealed that microglia engulf en passant pre-synapses without snipping off axons. C1q application alone did not significantly increase synaptic engulfment. However, C1q significantly increased synaptic engulfment when microglial surveillance of axons was induced by increased neuronal activity using DREADD, suggesting that neuronal activity plays an essential role to trigger microglial encounter with “eat-me” signals. Thus, our findings suggest that complement-dependent microglial synaptic engulfment is triggered and spatially controlled by neuronal activity.
| | 2020/9/12 12:05～12:30 Zoom A
MM2-04
ミクログリアの精神病理を探るためのヒト血液を用いた橋渡し研究
Microglia-focused psychiatric translational research using human bloods
*加藤 隆弘1
1. 九州大学大学院医学研究院 精神病態医学
*Takahiro A. Kato1
1. Department of Neuropsychiatry, Graduate School of Medical Sciences, Kyushu University
Microglia, immune cells in the CNS, have recently been highlighted to understand the underlying pathophysiology of various neuropsychiatric disorders. Postmortem brain analysis and PET imaging analysis are two major methods to estimate microglial activation in human subjects. However, by using the above methods, only a limited aspect of microglial activation can be measured. Dynamic analysis using fresh microglia in human brain is an ideal method, however technological and ethical considerations have limited the ability to conduct research using fresh human microglia.
To overcome this limitation, we have originally developed a technique to create directly induced microglia-like (iMG) cells from fresh human peripheral blood monocytes adding GM-CSF and IL-34 for 2 weeks, instead of brain biopsy (Ohgidani, Kato et al. Sci Rep 2014; PCT15/110004). Using the iMG cells, dynamic morphological and molecular-level analyses such as phagocytosis and cytokine releases are applicable.
We have used the iMG cells as surrogate cells of human microglia, and revealed previously-unknown dynamic pathophysiology of microglia in patients with Nasu-Hakola disease (Ohgidani, Kato et al. Sci Rep 2014), fibromyalgia (Sci Rep 2017) and rapid-cycling bipolar disorder (Ohgidani, Kato et al. Front Immunology 2017).
In addition, we have recently shown microglia-related pathophysiology using plasma such as human metabolome analysis focusing on the tryptophan-kynurenine pathway and neuron-related exosome analysis.
We believe that these indirect methods using human bloods shed new light on clarifying dynamic molecular pathologies of microglia in a variety of neuropsychiatric disorders.
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