シンポジウム（Symposium）

Symposium The future of glia research viewed by young glial researchers シンポジウム若手研究者から見たグリア研究の未来

7月25日（木）16:50～17:10　第10会場（万代島ビル　6F　会議室） 1S10e-1 グリアワールド: Ca²⁺イメージングが開拓した脳研究のフロンティア Yoshihisa Kudo（工藤佳久）東京医科大学　八王子医療センター　麻酔科 It was shortly after my establishment of Ca²⁺ imaging method, when I found the interesting sites of glia cells. On the way of developing my method, I might hear feint voices of glia cells, but I did not notice those signs. Since I myself was one of the neuron centric neuroscientists, I might miss or mishear their voice as noise or voices from neurons. I first recognized the dynamic activities as the characteristic Ca²⁺ concentration changes induced by t-ACPD, a metabotropic glutamate receptor agonist, on glia cells during the collaboration with a French researcher. However, during our contribution of the glial cell article (Barry et al. 1991), Cornell-bell et al. (1990) published their paper reporting the same phenomenon. I came to know that some of our published data as neuronal responses were misrecognition on activities of glial cells, especially astrocytes. Thereafter we put our focus on astrocytes and found specific activities of them in the dispersed cell culture and also slice culture preparation. For a while, we enjoyed the interesting properties of astrocytes by Ca²⁺ imaging, but I came to doubt if the responses we found in such artificial conditions were really physiological functions. Neuronal cells subjected to electrophysiology gave us the precisely same responses in every experimental preparation, and the features could be basically applicable to the study on large scale neuron networks. However, astrocyte altered their activities and even major structures according to the environment. To know the true functions of astrocytes and the other glial cells, we should use preparations in which glial cells would show their original functional features. When I came up this conclusion, I disappointed so much. At that time, it seemed to be impossible for me. However, recently, many outstanding young scientists participated in glia research. They established important methods to examine the true function of glial cells in vivo brain by introducing optogenetics into glial cells and made great advance in the imaging techniques. I believe now those evolved imaging techniques will cultivate the glia world further. I am expecting the participation of much more young researchers on this development and make the glia world much clearer by their power.		7月25日（木）17:10～17:38　第10会場（万代島ビル　6F　会議室） 1S10e-2 健康な脳の鍵を握る脳の中のメタコミュニケーション Hiromu Monai（毛内拡）^1,2 ¹お茶大理 ²理研CBS 神経グリア回路 The most popular target of neurophysiology has been neural circuits, which neurons connected each other through so-called synapses. This approach has been very successful in explaining the building blocks of the brain, but there is still a gap between our cognitive functions and the study of the synaptic interaction between neural circuits. Our cognitive functions, especially intelligence, are quite complex and we still don't know how neurons work together to achieve these functions. Besides neurons, our brains also contain blood vessels, glial cells, gliotransmission, neuromodulator, volume transmission, cerebrospinal fluid, ion concentrations, electric fields, extracellular spaces, and some lipids! A lot of research has been investigating how neurons talk to each other through synapses, but all these different components also have to function and communicate with each other. And I believe these components enable us to acquire complex cognitive functions. I think in the healthy brain, these other cells and molecules are engaged in very sophisticated and dynamic communication. It is what I call ""meta-communication"" and what I'm trying to reveal its unknown mechanism. Astrocytes are a kind of glial cell, and for a long time, we thought they are just supporting cells for neurons, such as maintenance of extracellular environment and energy supply to neurons. But now we know they are doing more than that, like information processing in the brain. Also, animals with higher intelligence and well-developed cognitive functions, like a cat or human, have more astrocytes per neuron. This fact suggests there could be a relationship between astrocytes and intelligence. I'm fascinated by the mystery of how meta-communication in the brain contributes to complex cognitive functions and intelligence. Now I'm looking at what happens if meta-communication fails in the brain. Extreme cases might be cerebrovascular diseases like stroke, and psychiatry diseases like depression. I want to study the mechanisms of how these conditions occur in the brain and also how we can help the brain to recover, by normalizing the meta-communication.

7月25日（木）17:38～18:06　第10会場（万代島ビル　6F　会議室） 1S10e-3 脳発達期におけるミクログリアの神経保護作用 Yuki Fujita（藤田幸）^1,2，Toru Nakanishi（中西徹）^1,3，Masaki Ueno（上野将紀）⁴，Toshihide Yamashita（山下俊英）^1,2,3,5 ¹大阪大院医分子神経科学 ²大阪大免疫学フロンティア研究センター ³大阪大院生命機能 ⁴新潟大脳研 ⁵大阪大院医創薬神経科学 Microglia are known as the resident immune cells in the central nervous system (CNS), and have diverse functions in physiological and pathological brain. We previously reported the neuroprotective function of microglia in the developing brain. Microglia accumulated along subcerebral projecting axon, and their levels peaked at postnatal day 3 to 7. Inactivation or ablation of microglia increased apoptosis in layer V subcerebral and callosal projection neurons and increased degeneration of their axons. We assessed candidate molecules for the neuroprotective role of microglia, and identified that microglia-derived insulin-like growth factor 1 (IGF1) supported the neuronal survival. Thus, microglia support the survival of neurons and axons in the postnatal brain. The next question is how microglia accumulate towards subcerebral projecting axon. Although it is well established that neuron-derived fractalkine (CX3CL1) mediates the interactions between neurons and CX3CR1-expressing microglia, the number of microglia did not decrease in the brain of Cx3cr1-deficient mice. This suggests that fractalkine-CX3CR1 signaling is not required for the migration of microglia. To assess the molecular mechanism of their interaction, we investigated whether microglia distribute along postnatal axons depending on the axon-derived factor. These results will help to understand how neuron-microglia communication determines axonal survival and degeneration in the developing brain.		7月25日（木）18:06～18:34　第10会場（万代島ビル　6F　会議室） 1S10e-4 翻訳リードスルーにより制御されるミエリンの形成と機能 Yoshinori Otani（大谷嘉典）^1,2，Nobuhiko Ohno（大野伸彦）³，Yoshihide Yamaguchi（山口宜秀）¹，Jing-Jing Cui（崔晶晶）¹，Hiroko Baba（馬場広子）¹ ¹東京薬科大学　薬学部　機能形態学 ²島根大学医学部解剖学講座（神経科学） ³自治医科大学医学部解剖学講座組織学部門 Translational readthrough is known as a key mechanism that expands the coding potential of the genomes from viruses to Drosophila. Recently, readthrough proteins, including large myelin protein zero (L-MPZ) (Yamaguchi et al., 2012), vascular endothelial growth factor extra form (VEGF-Ax) (Eswarappa et al., 2014), and aquaporin 4 extended isoform (AQP4ex) (De Bellis et al., 2017) have been identified in mammals. This suggests its importance in higher animals, although specific roles of these readthrough products have not been fully understood. L-MPZ is an isoform of myelin protein zero (P0), containing additional 63 amino acids at C-terminus by readthrough mechanism in various species including human (Yamaguchi et al., 2012). While L-MPZ is localized in the PNS myelin like P0, independent function of this protein is still uncertain. Another readthrough protein VEGF-Ax modulates canonical VEGF-mediated signaling, suggesting that the readthrough products may have different roles from original proteins. In order to clarify L-MPZ function in the PNS myelin, a mouse line (L-MPZ mice) that synthesizes only L-MPZ was generated by CRISPR-Cas9 system. The motor tests, and morphological and electrophysiological analyses indicated that replacement of P0 to L-MPZ caused progressive neuropathy with abnormal myelin, similar to Charcot-Marie-Tooth (CMT) disease in human. Heterozygous mice, which showed increased L-MPZ and decreased P0 levels in myelin, demonstrated various severity levels from normal to neuropathy phenotype. Thus, appropriate ratio of L-MPZ/P0 is critical for myelin formation and function. Furthermore, our study indicates a possibility of CMT pathogenesis caused by alteration of readthrough ratio in translation.