TOP ＞ 一般口演

一般口演 グリア機能 Glial Mechanisms 座長：飛田 秀樹（名古屋市立大学医学研究科）・小山 隆太（東京大学大学院薬学系研究科 薬品作用学教室） 2022年7月2日　14:00～14:15　沖縄コンベンションセンター 会議場B5～7　第4会場 3O04a1-01 Endoplasmic reticulum-plasma membrane contact sites in perisynaptic astrocytic processes: properties and effects *Audrey Denizot(1), María Fernanda Veloz Castillo(2), Corrado Calì(3), Erik De Schutter(1) 1. Okinawa Institute of Science and Technology, Computational Neuroscience Unit, Onna-Son, Japan, 2. Biological and Environmental Science and Engineering Division, King Abdullah University of Science and Technology, Thuwal, Saudi Arabia, 3. Department of Neuroscience, Neuroscience Institute Cavalieri Ottolenghi, University of Turin, Italy Keyword: Astrocyte, Calcium, Synapses, Modeling Astrocyte-neuron communication at tripartite synapses is mediated by calcium signals in perisynaptic astrocytic processes (PAPs), that are essential to brain function, from synaptogenesis to learning [1]. As single astrocytes can interact with thousands of synapses [2], they can potentially orchestrate information integration and transmission within various neural circuits simultaneously. Yet, as PAPs are usually too small to be resolved by diffraction-limited microscopy, the mechanisms that govern information processing at tripartite synapses remain poorly understood. Here, we combine electron microscopy, 3D mesh manipulation and stochastic computational modeling to provide new insights into the regulation of calcium activity in PAPs. First, we reconstruct 3D meshes of hippocampal tripartite synapses from electron microscopy, that we use to characterize endoplasmic reticulum-plasma membrane (ER-PM) contact sites in PAPs. Second, we implement an automated workflow that creates artificial realistic PAP meshes in 3D, characterized by various ER-PM contact site properties. Lastly, we use STEPS software [3] to perform reaction-diffusion simulations in those meshes, providing key insights on the effect of ER-PM contact sites on astrocyte calcium activity at tripartite synapses. REFERENCES [1] A. Verkhratsky and M. Nedergaard, “Physiology of Astroglia,” Physiol. Rev., vol. 98, no. 1, pp. 239–389, Jan. 2018, doi: 10.1152/physrev.00042.2016. [2] E. A. Bushong, M. E. Martone, Y. Z. Jones, and M. H. Ellisman, “Protoplasmic astrocytes in CA1 stratum radiatum occupy separate anatomical domains,” J. Neurosci. Off. J. Soc. Neurosci., vol. 22, no. 1, pp. 183–192, Jan. 2002. [3] I. Hepburn, W. Chen, S. Wils, and E. De Schutter, “STEPS: efficient simulation of stochastic reaction–diffusion models in realistic morphologies,” BMC Syst. Biol., vol. 6, no. 1, p. 36, 2012, doi: 10.1186/1752-0509-6-36. 2022年7月2日　14:15～14:30　沖縄コンベンションセンター 会議場B5～7　第4会場 3O04a1-02 母性因子がミクログリアを介して子の脳の発達に与える影響の解析 Analysis of the effect of maternal factor on the brain development of the child via microglia *定方 哲史(1)、高雄 啓三(2)、金子 涼輔(3)、飯島 崇利(4) 1. 群馬大学大学院医学系研究科、2. 富山大学医学薬学研究部行動生理学講座、3. 大阪大学大学院生命機能研究科、4. 東海大学医学部医学科基礎医学系分子生命科学 *Tetsushi Sadakata(1), Keizo Takao(2), Ryosuke Kaneko(3), Takatoshi Iijima(4) 1. Education and Research Support CenterGunma University Graduate School of Medicine, 2. Life Science Research Center, University of Toyama, 3. Laboratories for Integrated Biology, Graduate School of Frontier Biosciences, Osaka University, 4. Institute of Innovative Science and Technology, Tokai University Keyword: microglia Maternal antibodies are transferred to the blood of the child via the placenta and breast milk, and it is thought that their main function is to enhance the immunity of the newborn. On the other hand, abnormalities in the amount of antibodies in maternal plasma have been reported to be involved in autism, and a relationship between breastfeeding and IQ has also been suggested. We have recently found that maternal antibodies bind to microglial cells in the brains of mouse pups only during infancy. Furthermore, when we generated genetically modified mice in which maternal antibodies were not delivered to the offspring, we observed a decrease in the number of microglial cells, an increase in the overall cell density of the cerebral neocortex, and a decrease in the number of inhibitory neurons in the cerebral neocortex. In addition to further detailed anatomical analysis, we would like to conduct RNA-Seq and behavioral analysis to clarify the effects of microglial stimulated by maternal antibodies on brain development. As non-inflammatory roles of microglia become increasingly recognized as critical to normal neurodevelopment, it is important to consider how dysfunction in these processes might explain the seemingly disparate findings of immune dysfunction and aberrant synaptogenesis as seen in autism spectrum disorder. This study reveals the changes in microglia in the immature brain in response to maternal antibodies and the regulation of their functions in normal brain development. 2022年7月2日　14:30～14:45　沖縄コンベンションセンター 会議場B5～7　第4会場 3O04a1-03 ミクログリア成熟を制御する神経細胞微小核の細胞間伝播 Propagation of neuronal micronuclei regulates microglial maturation *鶴田 文憲(1)、矢野 更紗(2)、浅見 奈都(3) 1. 筑波大学生命環境系、2. 筑波大学生命環境科学研究科、3. 筑波大学生命環境学群生物学類 *Fuminori Tsuruta(1), Sarasa Yano(2), Natsu Asami(3) 1. Faculty of Life and Env Sci, Univ of Tsukuba, Tsukuba, Japan, 2. Grad Sch of Life and Env Sci, Univ of Tsukuba, Tsukuba, Japan, 3. Col of Biol Sci, Sch of Life and Env Sci, Univ of Tsukuba, Japan Keyword: microglia, micronuclei, cGAS-STING Microglia, resident macrophages in the central nervous system, change their state from amoeboid to ramified during the postnatal period. Morphological changes of microglia are regulated by not only the intrinsic pathway but also the signals from the local environment. Also, microglia exhibit highly diverse characteristics in a region-specific manner. Thus, it is thought that microglial maturation and diversity are influenced by the surrounding environment. However, niche signals underlying regional microglial diversity remain largely unknown. In this study, we identified that extracellular neuronal micronuclei regulate microglial characteristics in the vicinity of the cerebral cortex. We found that neurons passing through a dense region close to the pial surface of the developing neocortex gives rise to micronuclei and release them into the extracellular space. Moreover, neuron-derived micronuclei were found to be incorporated into microglia residing at Layer 1 and border-associated macrophage in meninges. Importantly, micronucleus incorporation resulted in activation of the cGAS-STING pathway, which delayed postnatal maturation of microglia from the amoeboid to ramified state. cGAS deletion indeed accelerated postnatal ramification of micronucleus-harboring microglia. Although micronuclei have been considered to emerge in cancers, these results demonstrate their physiological role as a novel mediator of intercellular communication that regulates microglial maturation. Our findings thus provide a mechanistical basis for microglial heterogeneity in the early-postnatal neocortex. 2022年7月2日　14:45～15:00　沖縄コンベンションセンター 会議場B5～7　第4会場 3O04a1-04 Unveiling the mechanism of methamphetamine-induced neuroinflammatory response: focus on astrocyte to microglia glutamatergic signaling *Canedo Teresa(1,2)、Silva Ana(1,3)、Andrade Elva(1)、Almeida Tiago(1,3)、Pombinho António(1)、Terceiro Ana(1,3)、Relvas João(1,2)、Summavielle Teresa(1,4) *Teresa Canedo Canedo(1,2), Ana Isabel Silva(1,3), Elva Bonifácio Andrade(1), Tiago Oliveira Almeida(1,3), António Pombinho(1), Ana Filipa Terceiro(1,3), João Bettencourt Relvas(1,2), Teresa Summavielle(1,4) 1. i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal, 2. Faculdade de Medicina da Universidade do Porto (FMUP), Porto, Portugal, 3. Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal, 4. ESS.PP, Escola Superior de Saúde do Politécnico do Porto, Porto, Portugal Keyword: Microglia, Astrocyte, Methamphetamine, Neuroinflammation Methamphetamine (Meth) is a highly addictive and neurotoxic psychostimulant, with high levels of worldwide use. It is now well accepted that upon the classic neuronal and behavioral effects, Meth also causes brain inflammation. We have recently shown that Meth cause both microglial expansion and activation. Although several studies pointed microglia activation as a possible major mediator of Meth-induced neuroinflammation/neurotoxicity, we have also shown that Meth cannot activate microglia in a cell-autonomous way. In fact, we have demonstrated that activation of microglia under Meth relies on an astrocyte - to - microglia crosstalk mediated by glutamate release from Meth-exposed astrocytes. We have also shown that this mechanism is driven by Meth-promoted TNF production leading to increased astrocytic glutamate release through IP3/Ca2+-dependent exocytosis. To gain new insight into astrocyte-derived glutamate induced microglia activation, here we unraveled which microglia glutamate receptors were mediating microglia activation by astrocyte-released glutamate. Using a library of antagonists/agonists of the metabotropic glutamate receptors, we identified both of glutamate receptors from group I (mGluR1 and mGluR5) as potential candidates. After a validation process complemented by a systematic review of the existing literature, we selected a modulator of the metabotropic glutamate receptor 1 (mGluR1) for in vivo evaluation. We found that antagonism of the mGluR1 is sufficient to prevent microglial expansion and activation under Meth exposure. Overall, here we identified mGluR1 as potential future therapeutic target to counteract Meth-induced microglia activation.