シンポジウム (Symposia)

ISN/JSN共催シンポジウム「シナプス再編におけるグリア細胞の役割」 Joint Symposium JSN+ISN: Glia-mediated synaptic remodeling
S2-1-1-1 Too much of a good-thing: Alferndtive (M2) activation and inhibition of hippocampal synapse matardtion ○Monica J. Carson¹, Yoshinori Otani¹, Deirdre S. Davis¹, Slawomir Sloniowski¹, Alfredo Hernandez¹, Victoria Senhechal¹, Michael Hsu¹, Jacqueline Gil¹, Andrea Tenner¹, Marco Colona¹, Craig V. Byus¹, Devin K Binder¹¹, Iryna M. Ethell¹ Center for Glial-Neuronal Interactions, School of Medicine, University of California, Riverside¹ Systemic inflammation is a common event in infancy and childhood and is associated with activation of microglia, the brain's tissue macrophage. Microglia are the only cells in the murine CNS that express the orphan receptor TREM2. Microglia express 20-fold higher levels of TREM2 during early post-natal development as compared to in adulthood. Neurons express putative TREM2 ligands (TREM2 binding activity). At all ages examined, microglia increase their expression of TREM2 in response to systemic immune challenge. However, elevated expression is sustained only when immune challenge occurs during the second post-natal week. Co-incident with the sustained microglial expression of TREM2, hippocampal neurons exhibit a delay in the normal developmental increase in excitatory vglut1+ synapses. Without TREM2, the developing hippocampus exhibits chronic M2 polarized inflammation, decreased numbers of vglut1+synapses, altered hippocampal responses to systemic immune challenge, and reduced susceptibility to PTZ-induced seizures. Taken together, our data suggest that the TREM2 pathway may be a novel neuronal-microglia regulatory pathway required to promote protective immunity during ordinary systemic inflammatory challenges encountered during childhood.	S2-1-1-2 グリアによる大脳皮質感覚野シナプス再編 Glia-induced remodeling of nuronal crcuits in the somatosensory cortex ○鍋倉淳一^1,2,3, 金善光^1,4, 和気弘明⁵, 江藤圭¹ ○Junichi Nabekura^1,2,3, Sun Kwan Kim^1,4, Hiroaki Wake⁵, Kei Eto¹ 自然科学研究機構　生理学研究所¹, クレスト², 総合研究大学院大学³, 慶熙大学⁴, 基礎生物学研究所⁵ National Inst. Physiological Sciences¹, JST Saitama, Japan², Sokendai, Hayama, Japan³, Kyung Hee University, Seoul, Korea⁴, NIBB, Okazaki, Japan⁵ Recent advance in imaging techniques, e.g. MRI and PET, allows us to understand the activation of various brain areas. However, due to their spatial limitation, it is difficult to observe more fine structures in vivo. Here, we introduce two evidences of dynamics of neuronal structures and the contribution of glia to their remodeling by using two photon microscopy. Real time imaging revealed that resting microglia, the primary immune cells in the brain, dynamically and directly monitors the local synaptic states. Resting microglial processes make brief (~5 min) and direct contacts with neuronal synapses. In the damaged brain the microglia-synapse contact periods were prolonged (~1 hour), frequently followed by the disappearance of presynaptic boutons. In addition, the neuronal hyperactivity often induced axonal swelling and a sporadic pathological membrane depolarization. Microglial process approached to and wrapped the swollen axon by detecting ATP released though a volume-activated chloride channel of swollen axon. As a result, microglial contact repolarized the membrane potential to rescue the neurons from excitotoxicity. Repeated observation of the same neuronal structures of the mouse cortex over several months reveals the dynamics of dendritic spines of somatosensory cortex in neuropathic pain. An increase of spine turnover in the S1 corresponding to the injured paw was limited during an early developing phase of neuropathic pain, in which preexisting stable spines preferentially eliminated. In this early phase, the activity of astrocyte in the S1 selectively enhanced. Activation of astrocyte could induce a release of thrombospondin, resulting in accelerating the spine turnover, which could the underlying mechanism of exaggerating the neuronal response in the somatosensory cortex to peripheral stimulation. An advance in imaging of fine structures in the living brain contributes to better understand the brain function in terms of synapse dynamics.
S2-1-1-3 ミクログリア分子時計によるミクログリアーシナプス相互作用とシナプス強度の制御 Microglial circadian clock controls diurnal changes in synaptic strength through microglia-synaptic interactions ○中西博^1,2 ○Hiroshi Nakanishi^1,2 九州大学大学院歯学研究院口腔機能分子科学分野¹, 独立行政法人科学技術振興機構、CREST² Dept Aging Sci and Phramacol, Fac of Dent Sci, Kyushu Univ, Fukuoka¹, Japan Science and Technology Agency, Core Research for Evolutional Science and Technology² There is accumulating evidence that microglia play crucial roles in synapse remodeling through interactions with synaptic structures. However, the precise molecular basis underlying the establishment of microglia-synapse interactions remains unclear. Here we show that cortical microglia contain intrinsic molecular clock and exhibit circadian expression of two microglia-specific molecules, P2Y₁₂ receptors (P2Y₁₂R) and cathepsin S (CatS), which are involved in microglial process extension and proteolytic modification of perisynaptic environment, respectively. The circadian expressions of P2Y₁₂R and CatS were generated by CLOCK-BMAL1-regulated transcriptional negative-feedback loops. In addition, we also found the diurnal variations in microglial process extension, microglia-synapse interactions and synaptic strength in the cerebral cortex, peaked during the dark phase, which were disappeared by treatment with clopidogrel, P2Y₁₂R inhibitor, or genetic deletion of CatS. These results suggest that the molecular clock-driven circadian expression of P2Y₁₂R and CatS in cortical microglia is responsible for diurnal changes in synaptic strength through microglia-synapse interactions. The present findings will not only cultivate better understanding of synaptic homeostasis, but also may aid in understanding how biological rhythm dysfunctions are involved in the etiology of neuropsychiatric disorders.	S2-1-1-4 Role of gliotransmitters in cognition ○Justin Lee¹ Center for Functional Connectomics, Korea Institute of Science and Technology¹ Glial cells are non-neuronal cells that occupy most of the brain regions. In certain regions, the percentage can go up to 90% of the population of brain cells. Despite their importance, their role has been shadowed by the dominance of studies on neurons. Now, the various roles of glial cells are beginning to emerge and recent reports demonstrate their surprising roles in brain functions, even in cognition. Our laboratory has been investigating the role of astrocytes, which are the major cell type of glia. Just like neurons, astrocytes release various transmitters like glutamate, GABA, ATP, d-serine, taurine, and etc. Unlike neurons, astrocytes release these transmitters through specialized ion channels. The released “gliotransmitters” participate in synaptic transmission, synaptic modulation, and synaptic plasticity. Ultimately, gliotransmitters influence the cognitive behaviors, such as learning and memory, movement, sleep, and emotion. Because causes of many brain related diseases are still unknown, perhaps due to too much focus on neuronal dysfunction, glial cells should provide new insights to the direct causes of various neurological disorders and neurodegenerative diseases, such as Alzheimer disease, Parkinson’s disease, Huntington’s disease, sleep and movement disorders, learning and memory impairments, and etc. The study of glial cells and their interaction with neurons will shed light on many of those unsolved mysteries of the brain.
S2-1-1-5 アストロサイトによるシナプス再編 Synaptic remodeling by astrocytes ○小泉修一¹ ○Schuichi Koizumi¹ 山梨大学大学院医学工学総合研究部医学学域薬理学¹ Dept Neuropharmacol, Facul Med, Univ Yamanashi¹ It has become apparent that glial cells control a big variety of brain functions such as synaptic transmission, microcirculation and synaptic remodeling. Synaptic remodeling consists of two distinct events, i.e., synaptic elimination and formation. As for synaptic elimination, microglial phagocytosis plays a key role. As for synaptic formation, it has been reported that astrocytes play pivotal roles, i.e., they could control synapse formation either by a physical contact to neurons or by producing diffusible molecules. Here, however, we show that astrocytes are involved in both synaptic formation and elimination in the pathophysiological conditions. After sciatic nerve injuries, astrocytes in somatosensory cortex(S1) become activated and produce diffusible molecules, among which thrombospondins are involved in both neuropathic pain and synaptic formation. After middle cerebral artery occlusion, astrocytes in the striatum are activated and become a phagocytic phenotype. Such astrocytic modal shift would greatly affect synaptic remodeling and synaptic transmission. We also discuss molecular mechanisms underlying these astrocytic modal shifts.

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