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Spatiotemporal regulation of glutamate distribution by transporters (EAATs/VGLUTs) and implications in neuropsychiatric disorders

開催日 2014/9/13
時間 9:00 - 11:00
会場 Room E(301)
Chairperson(s) 田中 光一 / Kohichi Tanaka (東京医科歯科大学難治疾患研究所分子神経科学分野 / Medical Research Institute & CBIR, Tokyo Medical & Dental University, Japan)
木下 専 / Makoto Kinoshita (名古屋大学大学院理学研究科生命理学専攻 / Department of Molecular Biology, Nagoya University Graduate School of Science, Japan)

小脳バーグマングリアのCDC42EP4-セプチン複合体はGLAST を平行線維-プルキンエ細胞間シナプス近傍に集積させることでグルタミン酸クリアランスと運動学習を促進する
CDC42EP4/septin-dependent localization of GLAST to parasynaptic domains of Bergmann glia facilitates glutamate clearance from the parallel fiber-Purkinje cell synapses and motor learning

  • S3-E-1-3
  • 上田(石原) 奈津実 / Natsumi Ageta-Ishihara:1 山崎 真弥 / Maya Yamazaki:2 今野 幸太郎 / Kohtarou Konno:3 中山 寿子 / Hisako Nakayama:4 阿部 学 / Manabu Abe:2 橋本 謙二 / Kenji Hashimoto:5 西岡 朋生 / Tomoki Nishioka:6 貝淵 弘三 / Kozo Kaibuchi:6 宮川 剛 / Tsuyoshi Miyakawa:7,8 橋本 浩一 / Kouichi Hashimoto:4 渡辺 雅彦 / Masahiko Watanabe:3 崎村 建司 / Kenji Sakimura:2 木下 専 / Makoto Kinoshita:1 
  • 1:名大・理・生命理学 / Dept Mol Biol, Grad Sch Sci, Nagoya Univ, Nagoya, Japan 2:新潟大・脳研・細胞生物 / Dept Cell Neurobiol, Brain Res Inst, Niigata Univ, Niigata, Japan 3:北大・医・解剖 / Dept Anat, Grad Sch Med, Hokkaido Univ, Sapporo, Japan 4:広大・医歯薬・神経生理 / Dept Neurophysiol, Grad Sch Biomedical & health Sci, Hiroshima Univ, Hiroshima, Japan 5:千葉大・社会精神保健教育研究センタ- / Cent Forensic Mental Hlth, Chiba Univ, Chiba, Japan 6:名大・医・神経情報薬理 / Dept Cell Pharm, Grad Sch Med, Nagoya Univ, Nagoya, Japan 7:生理研・行動様式解析室 / Cent for Gene Anal of Behavior, NIPS, Okazaki, Japan 8:藤田保健衛生大・総医研・システム医科学 / Div System Med Sci, Fujita Health Univ, Toyoake, Japan 

CDC42EP1-5/BORG1-5, a family of small GTPase effector proteins, interact with GTP-bound CDC42 or the septin heterooligomers in a mutually exclusive manner, but their physiological roles are unknown. We find that CDC42EP4 in the mouse cerebellar cortex is expressed exclusively in Bergmann glia, in which CDC42EP4 localizes to specific microdomains facing dendritic spines of Purkinje cells. Biochemical analysis of cerebellar lysate indicates that CDC42EP4 is in complex with septins (SEPT2/3/4/5/6/7/8/10/11) and the glutamate transporter GLAST, but not with CDC42. In Cdc42ep4-/- Bergmann glia, GLAST is physically dissociated from septins and delocalized away from the parallel fiber-Purkinje cell (PF-PC) synapses. Patch-clamp analysis reveals that treatment of cerebellar slices with a glutamate transporter inhibitor, TBOA, elicits augmented inward current in Cdc42ep4-/- PCs, suggesting potential insufficiency of glutamate-buffering capacity in Cdc42ep4-/- Bergmann glia. Concordantly, a systematic battery of behavioral tests pinpoints motor learning defects in the balance beam test. Together, we conclude that CDC42EP4-dependent interaction with septins is required for the parasynaptic localization and efficiency of GLAST to achieve optimal clearance of extracellular glutamate from PF-PC synapses and cerebellum-dependent motor learning.

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