TOP ＞ 若手道場

若手道場 アストロサイト 7月7日（金）　16:00-16:45　Room D 2W③-1 Anatomical, molecular and functional survey of brain wide astrocyte ensembles representing distinct experiences 加瀬田　晃大, 長井　淳 理化学研究所 脳神経科学研究センター Kodai Kaseda, Jun Nagai RIKEN Center for Brain Science Astrocytes tile the entire central nervous system to maintain brain homeostasis by supporting metabolism and re-uptake of extracellular ions and neurotransmitters. Recent studies have suggested that astrocytes regulate animal behaviors, including both appetitive- and aversive-learning experiences. However, it remains elusive whether separable ensembles of astrocytes regulate distinct behavior. Here, we aim to address this question by advantageous tools for quantifying anatomy position, molecular properties, and the causal impact of astrocytes that respond to distinct valence-experience. We found that anatomically distinct astrocyte ensembles respond to different valence-stimuli and these ensembles have molecular phenotyping. Whole brain mapping revealed distinct distributions of activated astrocytes that are responsive to an appetitive or aversive stimulation. Next, we performed meta-analyses of single cell RNA-seq dataset to survey the molecular signatures of such astrocytes. Our data suggest that otherwise-indistinguishable astrocytes responding to appetitive and aversive stimuli may be anatomically and molecularly separable ensembles. We will also report our pilot experiments to reveal the circuits and behavioral functions of such astrocytes. 7月7日（金）　16:00-16:45　Room D 2W③-2 アレキサンダー病において変異アストロサイトが引き起こす白質変性のメカニズム Mechanisms underlying mutant astrocyte-mediated white matter degeneration in Alexander disease 久保田　友人1,2, 繁冨　英治1,2, 齋藤　光象1,2, 篠崎　陽一1,2, 小林　憲司1,2, 田中　謙二3, 大野　伸彦4, 小泉　修一1,2 1. 山梨大　院医　薬理, 2. 山梨GLIAセンター, 3. 慶應大　医　先端医脳科学, 4. 自治医大　医　解剖 Yuto Kubota1,2, Eiji Shigetomi1,2, Kozo Saito1,2, Youichi Shinozaki1,2, Kenji Kobayashi1,2, Kenji Tanaka3, Nobuhiko Ohno4, Schuichi Koizumi1,2 1. Dept. Neuropharmacol., Interdisc. Grad. Sch. Med., Univ. Yamanashi Alexander disease (AxD), a rare neurodegenerative disease, is caused by the mutation of GFAP gene whose expression is enriched in astrocytes. Thus, AxD is “a primary astrocyte disease”. AxD patients mainly show severe neurological symptoms such as psychomotor developmental delay, motor deficits etc. and white matter degeneration in their brains. However, molecular pathogenesis leading from GFAP mutation to white matter degeneration are not well understood, although AxD astrocytes are thought to gain neurotoxicity. Here, we analyzed the structural changes in the corpus callosum (CC) of AxD model mice carrying human mutant GFAP (Tanaka et al., GLIA, 2007). We found followings. (1) Immunohistochemical data show that non-myelinated and non-axonal area in the CC was markedly increased in AxD compared to wild-type (WT) mice. (2) AxD astrocytes mainly occupied such non-myelinated area, suggesting that AxD astrocytes should contribute to local white matter degeneration. (3) AxD astrocytes highly expressed Galectin-3 and lipocalin 2, both of which are thought to control astrocytic phagocytosis. (4) Electron microscopic analysis show that AxD astrocytes engulfed myelin, but not WT. Together, all these findings suggest that AxD astrocytes may phagocytose myelin by acquiring their abnormal phagocytic ability, thereby leading to white matter degeneration and various neurological symptoms. 7月7日（金）　16:00-16:45　Room D 2W③-3 てんかん誘導性神経炎症におけるYAPを介したグルタミン合成酵素発現機構の役割 The role of YAP-mediated glutamine synthetase expression in seizure-induced neuroinflammation 那須　優介1,2, 岸川　咲吏1, 照沼　美穂1 1. 新潟大学　口腔生化学, 2. 新潟大学　歯周診断・再建学 Yusuke Nasu1,2, Sari Kishikawa1, Miho Terunuma1 1. Div. of Oral Biochem., Niigata Univ., 2. Div. of Periodontol., Niigata Univ. Astrocytes, one of the major glial cells in the central nervous system, are the only cell type that express glutamine synthetase (GS), which metabolize glutamate and ammonia to form glutamine, and protect neurons from neurotoxicity. Previous reports showed that GS expression in the liver is regulated by Yes-associated protein (YAP), but it remains unclear whether YAP also regulates GS in the brain.Here, we report that YAP is a regulator of astrocytic GS using rat primary cultured astrocytes. Pharmacological inhibition of YAP nuclear localization reduced GS expression. Astrocytes exposed to excessive glutamate and NH4Cl reduced GS, YAP nuclear translocation and cytosolic YAP. Furthermore, XMU-MP-1, an inhibitor of the Hippo pathway which enhances YAP nuclear localization, promoted nuclear translocation of YAP and prevented GS downregulation even at high glutamate and NH4Cl condition. Finally, we investigated the effect of XMU-MP-1 in kainic acid-injected mice, model of status epilepticus, which is characterized by GS downregulation and neuroinflammation in the hippocampus. As we expected, XMU-MP-1 improved GS levels and inflammation. Together, our results suggest that targeting Hippo-YAP signaling pathway may become a novel therapeutic for epilepsy.