The role of ambient GABA in cerebelllar foliation

• Project/Area Number: 23500444
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurochemistry/Neuropharmacology
• Research Institution: Tokoha University (2013); Hamamatsu University School of Medicine (2011-2012)
• Principal Investigator: KUMADA Tatsuro 常葉大学, 保健医療学部, 教授 (00402339)
• Co-Investigator(Renkei-kenkyūsha): FUKUDA Atsuo 浜松医科大学, 医学部, 教授 (50254272) ; INOUE Koichi 浜松医科大学, 医学部, 准教授 (80345818)
• Research Collaborator: FURUKAWA Tomonori 浜松医科大学, 医学部, 技術補佐員 (60402369)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2013: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2012: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2011: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 小脳 / 細胞外GABA / GABAA受容体 / 小脳顆粒細胞 / 小脳皮質 / 葉形成 / GABA / 細胞分裂 / 神経発生

Research Abstract

Although distribution of GABA-A receptors and GABA-A receptor-mediated responses (excitability) are dynamically changed during stages of cerebellar morphogenesis, its roles on foliation and lobulation of cerebellar cortex have still remained unknown. Here, we addressed this issues by using various imaging methods and in vivo blockade experiments. Optical imaging method of extracellular GABA linked to enzymatic reaction of GABase enabled us to show temporal abundance of ambient GABA in the outer EGL region which have Granule precursor cells (GPCs). We also show that in vivo blockade of GABA-A receptor perturb the proliferation of these GPCs in the the posterior vermis of the early neonatal cerebellum. Furthermore, we have investigated the interaction between GABA-A receptor and sonic hedgehog (SHH) singlings by histochemical and Calcium imaging technique and suggested that SHH signalings seemed not to affect the GABA-A receptor-mediated responses.

Research Products

• [Journal Article] Activity-dependent endogenous taurine release facilitates excitatory neurotransmission in the neocortical marginal zone of neonatal rats (2014)
  • Author(s): Qian, T., et al.,
  • Journal Title: Front Cell Neurosci Volume: 8 Pages: 33-33
  • DOI: 10.3389/fncel.2014.00033
  • Peer Reviewed / Open Access
• [Journal Article] Accumulation of GABAergic neurons, causing a focal ambient GABA gradient, and downregulation of KCC2 are induced during microgyrus formation in a mouse model of polymicrogyria (2014)
  • Author(s): Wang, T., Kumada, T., Morishima, T., Iwata, S., Kaneko, T., Yanagawa, Y., Yoshida, S. and Fukuda, A
  • Journal Title: Cereb. Cortex Volume: 24 Pages: 1088-1101
  • Peer Reviewed
• [Journal Article] Accumulation of GABAergic neurons, causing a focal ambient GABA gradient, and downregulation of KCC2 are induced during microgyrus formation in a mouse model of polymicrogyria (2014)
  • Author(s): Wang T, Kumada T, Morishima T, Kaneko T, Yanagawa Y, Yoshida S, Fukuda A
  • Journal Title: Cereb. Cortex Volume: in press Pages: 1088-1101
  • DOI: 10.1093/cercor/bhs375
  • Peer Reviewed
• [Journal Article] De Novo Mutations in GNAO1, Encoding a Gαo Subunit of Heterotrimeric G Proteins, Cause Epileptic Encephalopathy (2013)
  • Author(s): Nakamura, K., Kodera, H., Akita, T., Shiina, M., Kato, M., Hoshino, H., Terashima, H., Osaka, H., Nakamura, S., Tohyama, J., Kumada, T., Furukawa, T., Iwata, S., Shiihara, T., Kubota, M., Miyatake, S., Koshimizu, E., Nishiyama, K., Nakashima, M., Tsurusaki, Y., Miyake, N., Hayasaka, K., Ogata, K., Fukuda, A., Matsumoto, N., and Saitsu, H
  • Journal Title: Am. J. Hum. Genet Volume: 93 Pages: 496-505
  • Peer Reviewed
• [Journal Article] Pre- and post-synaptic switches of GABA actions associated with Cl- homeostatic changes are induced in the spinal nucleus of the trigeminal nerve in a rat model of trigeminal neuropathic pain (2013)
  • Author(s): Wei, B., Kumada, T., Furukawa, T., Inoue, K., Watanabe, M., Sato, K. and Fukuda, A
  • Journal Title: Neuroscience Volume: 228 Pages: 334-348
  • Peer Reviewed
• [Journal Article] Pre- and post-synaptic switches of GABA actions associated with Cl^- homeostatic changes are induced in the spinal nucleus of the trigeminal nerve in a rat model of trigeminal neuropathic pain (2013)
  • Author(s): Wei, B., et al,
  • Journal Title: Neursocience Volume: 228 Pages: 334-348
  • DOI: 10.1016/j.neuroscience.2012.10.043
  • Peer Reviewed
• [Journal Article] De Novo mutations in GNAO1, encoding a Gαo subunit of heterotrimeric G proteins, cause epileptic encephalopathy. (2013)
  • Author(s): Nakamura, K., et al.,
  • Journal Title: Am J Hum Genet. Volume: 93 Pages: 496-505
  • DOI: 10.1016/j.ajhg.2013.07.014
  • Peer Reviewed
• [Journal Article] Accumulation of GABAergic neurons, causing a focal ambient GABA gradient, and downregulation of KCC2 are induced during microgyrus formation in a mouse model of polymicrogyria. (2013)
  • Author(s): Wang, T., et al,
  • Journal Title: Cereb. Cortex Volume: in press
  • Peer Reviewed
• [Journal Article] Guidepost neurons for the lateral olfactory tract : Expression of metabotropic glutamate receptor 1 and innervation by glutamatergic olfactory bulb axons (2012)
  • Author(s): Hirata, T., Kumada, T., Kawasaki, T., Furukawa, T., Aiba, A., Conquet, F., Saga, Y. and Fukuda, A
  • Journal Title: Dev. Neurobiol Volume: 72 Pages: 1559-1576
  • Peer Reviewed
• [Journal Article] Taurine inhibits the K+-Clcotransporter KCC2 to regulate embryonic Cl- homeostasis via the with-no-lysine (WNK) protein kinase signaling pathway (2012)
  • Author(s): Inoue, K., Furukawa, T., Kumada, T., Yamada, J., Wang, T., Inoue, R. and Fukuda, A
  • Journal Title: J. Biol. Chem Volume: 287 Pages: 20839-20850
• [Journal Article] Taurine Inhibits K+-Cl- Cotransporter KCC2 to Regulate Embryonic Cl- Homeostasis via With-no-lysine (WNK) Protein Kinase Signaling Pathway (2012)
  • Author(s): Inoue K, Furukawa T, Kumada T, Yamada J, Wang T, Inoue R, Fukuda A
  • Journal Title: J. Biol Chem Volume: 287 Pages: 20839-20850
  • DOI: 10.1074/jbc.m111.319418
  • Peer Reviewed
• [Journal Article] Guidepost neurons for the lateral olfactory tract: expression of metabotropic glutamate receptor 1 and innervation by glutamatergic olfactory bulb axons (2012)
  • Author(s): Hirata, T., Kumada, T., Kawasaki, T., Furukawa, T., Aiba, A., Conquet, F., Saga, Y. and Fukuda, A.
  • Journal Title: Dev. Neurobiol. Volume: (in press) Pages: 1559-1576
  • DOI: 10.1002/dneu.22030
  • Peer Reviewed
• [Presentation] Regional difference in GABA_A Receptor Mediated Ca^<2+> responses of radially migrating neurons in the mouse embryonic neocortex (2013)
  • Author(s): Kumada, T., Nakanishi, Y., Furukawa, T. and Fukuda, A
  • Organizer: The 23th CDB meeting
  • Place of Presentation: Kobe, Japan
• [Presentation] 大脳皮質の発生過程における移動神経細胞の領域特異的なGABA_A受容体応答 (2013)
  • Author(s): 熊田竜郎, 中西康彦, 古川智範, 福田敦夫
  • Organizer: 第40回日本脳科学学会
  • Place of Presentation: 浜松
• [Presentation] Activity dependent release of taurine facilitates the excitatory neurotransmission in the marginal zone of developing cerebral cortex (2013)
  • Author(s): Kumada, T., Qian, T., Nakamura, M., Furukawa, T., Yamada, J., Akita, T., Kilb, W., Luhmann, H.J., Nakahara, D. and Fukuda, A
  • Organizer: 第36回日本神経科学大会
  • Place of Presentation: 京都
• [Presentation] マウス大脳皮質の移動神経細胞における領域特異的なGABA_A受容体応答. 文部科学省科学研究費補助金「新学術領域・動く細胞と秩序」 (2013)
  • Author(s): 熊田竜郎
  • Organizer: 第7回領域班会議
  • Place of Presentation: 名古屋
• [Presentation] 活動依存的な内因性タウリンの放出が新生ラット大脳新皮質辺縁帯の興奮性シナプス伝達を促進する (2013)
  • Author(s): 熊田竜郎, 千 太哲, 中村直人, 古川智範, Werner Kilb. Heiko J Luhmann. 中原大一郎, 福田敦夫
  • Organizer: 第90回日本生理学会大会
  • Place of Presentation: 東京
• [Presentation] マウス大脳皮質の移動神経細胞における領域特異的なGABA_A￥受容体応答 (2013)
  • Author(s): 熊田竜郎
  • Organizer: 冬の班会議
  • Place of Presentation: 神戸
• [Presentation] マウス大脳皮質の移動神経細胞における領域特異的なGABAA受容体応答 (2013)
  • Author(s): 熊田竜郎
  • Organizer: 文部科学省科学研究費補助金「新学術領域・動く細胞と秩序」第7回領域班会議
  • Place of Presentation: 名古屋
• [Presentation] 神経活動依存的に放出されるタウリンは大脳皮質の辺縁帯における興奮性の神経伝達を促進する (2013)
  • Author(s): 熊田竜郎
  • Organizer: 第36回日本神経科学大会
  • Place of Presentation: 京都
• [Presentation] 大脳皮質の発生過程における移動神経細胞の領域特異的なGABAA受容体応答 (2013)
  • Author(s): 熊田竜郎
  • Organizer: 第40回日本脳科学学会
  • Place of Presentation: 浜松
• [Presentation] Activity-dependent endogenous taurine release facilitates the excitatory neurotransmission in the neocortical marginal zone of neonatal rats. (2013)
  • Author(s): 熊田竜郎ら
  • Organizer: 第90 回日本生理学会大会
  • Place of Presentation: 東京
• [Presentation] Regional difference in GABA A Receptor Mediated Ca2+ responses of radially migrating neurons in the mouse embryonic neocortex. (2013)
  • Author(s): Kumada, T., et al,
  • Organizer: The 23th CDB meeting, "Building multicellular systems from Cellular Cross-Talk"
  • Place of Presentation: 神戸
• [Presentation] Pre- and post-synaptic switches of GABA actions in the spinal nucleus of the trigeminal nerve in a rat model of trigeminal neuropathic pain (2012)
  • Author(s): Kumada, T., Wei, B., Furukawa, T., Inoue, K., Watanabe, M., Sato, K. and Fukuda, A
  • Organizer: The 12th Kyungpook-Hamamatsu Joint Medical Symposium Hamamatsu Meeting
  • Place of Presentation: Hamamatsu, Japan
  • Year and Date: 2012-09-26
• [Presentation] Intracellular taurine inhibits the functioning of KCC2 protein by phosphorylation via with-no-lysine (WNK) protein kinase pathway (2012)
  • Author(s): Fukuda, A., Inoue, K., Furukawa, T., Yamada, J., Kumada, T., Wang, T. and Inoue, R
  • Organizer: The 8th FENS Forum of Neuroscience
  • Place of Presentation: Barcelona, Spain
• [Presentation] 活動依存的な内因性タウリンの放出が新生ラット大脳新皮質辺縁体の興奮性シナプス伝達を促進する (2012)
  • Author(s): 熊田竜郎, 千太哲, 中村直人, 古川智範, Kilb Werner, Luhmann Heiko J., 中原大一郎, 福田敦夫
  • Organizer: 生理学研究所研究会
  • Place of Presentation: 岡崎
• [Presentation] マウス大脳皮質の移動神経細胞における領域特異的なGABA_A受容体応答 (2012)
  • Author(s): 熊田竜郎, 中西康彦, 古川智範, 江川潔, 福田敦夫
  • Organizer: 第59回中部生理学会
  • Place of Presentation: 岡崎
• [Presentation] 胎仔脳の移動細胞におけるカルシウム振動の領域による相違 (2012)
  • Author(s): 熊田竜郎, 中西康彦, 古川智範, 江川潔, 福田敦夫
  • Organizer: 第35回日本神経科学大会
  • Place of Presentation: 名古屋
• [Presentation] 発達期大脳皮質における細胞外GABA とタウリンの分布の違いとそれに伴う移動神経細胞の異なるGABAA受容体応答 (2012)
  • Author(s): 熊田竜郎
  • Organizer: 平成24年度新学術領域「動く細胞と場のクロストークによる秩序の生成」夏の班会議
  • Place of Presentation: 神奈川
• [Presentation] タウリン-WNK-SPAK/OSR1 シグナルによる神経特異的イオン輸送体KCC2の活性制御と大脳皮質構築への影響の検討 (2012)
  • Author(s): 井上浩一, 古川智範, 熊田竜郎, 福田敦夫
  • Organizer: 平成24年度新学術領域 「神経細胞の多様性と大脳新皮質の構築」夏の班会議
  • Place of Presentation: 仙台
• [Presentation] 胎仔脳の移動細胞におけるカルシウム振動の領域による相違 (2012)
  • Author(s): 中西康彦, 熊田竜郎, 古川智範, 江川潔, 福田敦夫
  • Organizer: 第89回日本生理学会大会
  • Place of Presentation: 長野
• [Presentation] 細胞内タウリンによるKCC2 蛋白活性のリン酸化を介した修飾 (2012)
  • Author(s): 福田敦夫, 井上浩一, 古川智範, 山田順子, 熊田竜郎, 王 天英, 井上利恵子
  • Organizer: 第89回日本生理学会大会
  • Place of Presentation: 長野
• [Presentation] 活動依存的な内因性タウリンの放出が新生ラット大脳新皮質辺縁帯の興奮性シナプ ス伝達を促進する (2012)
  • Author(s): 熊田竜郎ら
  • Organizer: 生理学研究所研究会「神経シナプス伝達の時空間ダイナミクス」
  • Place of Presentation: 岡崎
• [Presentation] マウス大脳皮質の移動神経細胞における領域特異的なGABA A受容体応答 (2012)
  • Author(s): 熊田竜郎ら
  • Organizer: 第59回中部生理学会
  • Place of Presentation: 岡崎
• [Presentation] Pre- and post-synaptic switches of GABA actions in the spinal nucleus of the trigeminal nerve in a rat model of trigeminal neuropathic pain. (2012)
  • Author(s): Kumada, T., et al,
  • Organizer: 第12回慶北-浜松合同医学シンポジウム
  • Place of Presentation: 浜松
• [Presentation] Regional difference in calcium oscillation of radially migrating neurons in the mouse embryonic neocortex. (2012)
  • Author(s): 熊田竜郎ら
  • Organizer: 第35回日本神経科学大会
  • Place of Presentation: 名古屋
• [Presentation] Intracellular taurine inhibits the functioning of KCC2 protein by phosphorylation via with-no-lysine (WNK) protein kinase pathway. (2012)
  • Author(s): Fukuda, A., et al,
  • Organizer: 8th FENS Forum of Neuroscience
  • Place of Presentation: Barcelona, Spain
• [Presentation] Intracellular taurine modulates KCC2 function by phosphorylation. (2012)
  • Author(s): Fukuda, A., et al,
  • Organizer: 第89回日本生理学会大会
  • Place of Presentation: 長野
• [Presentation] Regionally differential calcium oscillation of radially migrating cells in embryonic cortex. (2012)
  • Author(s): Nakanishi, Y., et al,
  • Organizer: 第89回日本生理学会大会
  • Place of Presentation: 長野
• [Presentation] Taurine prevents KCC2 from functioning in a phosphorylation-dependent manner to render embryonic Cl- homeostasis (2011)
  • Author(s): Inoue, K., Furukawa, T., Yamada, J., Kumada, T., Wang, T., Inoue, R. and Fukuda, A
  • Organizer: 41st Annual Meeting, Society for Neuroscience
  • Place of Presentation: Washington, D.C., USA
• [Presentation] 発達期大脳皮質における細胞外GABA とタウリンの分布の違いとそれに伴う移動神経細胞の異なるGABA_A受容体応答 (2011)
  • Author(s): 熊田竜郎
  • Organizer: 平成23年度新学術領域「動く細胞と場のクロストークによる秩序の生成」の班会議
  • Place of Presentation: 大阪
• [Presentation] Temporal paracrine GABA and KCC2 downregulation underlie the formation of microgyrus in a model of focal cortical malformation (2011)
  • Author(s): Fukuda, A., Wang, T., Kumada, T., Morishima, T. and Yanagawa, Y
  • Organizer: 第34回日本神経科学大会
  • Place of Presentation: 横浜
• [Presentation] 実験的皮質形成異常の成因におけるパラクリンGABA とKCC2発現抑制の役割 (2011)
  • Author(s): 福田敦夫, 王 天英, 熊田竜郎, 森島寿貴, 柳川右千夫
  • Organizer: 第88回日本生理学会大会 第116回日本解剖学会総会・全国学術集会
  • Place of Presentation: 横浜
• [Presentation] Ambient GABA released from Bergmann glial cells promotes proliferation of cerebellar granule cell precursors. (2011)
  • Author(s): Fukuda, A., et al,
  • Organizer: 41st Annual Meeting, Society for Neuroscience.
  • Place of Presentation: Washington, D.C.
• [Presentation] Taurine prevents KCC2 from functioning in a phosphorylation-dependent manner to render embryonic Cl- homeostasis. (2011)
  • Author(s): Inoue, K., et al.,
  • Organizer: 41st Annual Meeting, Society for Neuroscience.
  • Place of Presentation: Washington, D.C.
• [Book] 脳科学辞典 (2013)
  • Author(s): 秋田天平, 熊田竜郎, 福田敦夫
  • Publisher: 塩素チャネル
• [Book] Multimodal GABA_A Receptor Functions on Cell Development. In : Comprehensive Developmental Neuroscience (Rubenstein, J., Rakic, P., eds) (2013)
  • Author(s): Fukuda, A., Nakanishi, Y., Kumada, T., and Furukawa. T
  • Publisher: Oxford : Elsevier
• [Book] Migration in the cerebellum. In : Comprehensive Developmental Neuroscience "Cellular Migration and Formation of Neuronal Connections (2013)
  • Author(s): Komuro, Y., Kumada, T., Ohno, N., Foote, K. D., and Komuro, H
  • Publisher: Oxford : Elsevier
• [Book] Cerebellar patterning. In : Comprehensive Developmental Neuroscience, "Patterning and Cell Type Specification in the Developing CNS and PNS" (2013)
  • Author(s): Fahrion, J. K., Komuro, Y., Ohno, N., Littner, Y., Nelson, C., Kumada, T., Lamb, B., and Komuro, H
  • Publisher: Oxford : Elsevier
• [Book] Migration in the cerebellum. In: Comprehensive Developmental Neuroscience “Cellular Migration and Formation of Neuronal Connections (2013)
  • Author(s): Komuro, Y. et al.,
  • Total Pages: 17
  • Publisher: Oxford: Elsevier
• [Book] Cerebellar patterning. In: Comprehensive Developmental Neuroscience, “Patterning and Cell Type Specification in the Developing CNS and PNS” (2013)
  • Author(s): Fahrion, J. K.,et al.,
  • Total Pages: 13
  • Publisher: Oxford: Elsevier
• [Book] Granule Cell Migration and Differentiation, Handbook of the Cerebellum and Cerebellar Disorders, Chapter 11 (2012)
  • Author(s): Komuro, Y., Fahrion, J. F., Foote, K.D., Fenner K. B., Kumada, T., Ohno, N., and Komuro, H
• [Book] Handbook of the Cerebellum and Cerebellar Disorders. (2012)
  • Author(s): Komuro, Y., et al,
  • Total Pages: 19
  • Publisher: Granule Cell Migration and Differentiation.
• [Book] Comprehensive Developmental Neuroscience. (2012)
  • Author(s): Fukuda, A., et al,
  • Publisher: Elsevier
• [Book] Neuronal cell migration in fetal alcohol syndrome. Handbook of Behavior, food and Nutrition, Chapter 182 (2011)
  • Author(s): Kumada, T., Komuro, Y., Li, Y., Littner, Y., and Komuro, H