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発達脳におけるシナプス除去と機能成熟に関与するシグナル伝達系

Research Project

Project/Area Number 12053226
Research Category

Grant-in-Aid for Scientific Research on Priority Areas

Allocation TypeSingle-year Grants
Review Section Biological Sciences
Research InstitutionKanazawa University

Principal Investigator

狩野 方伸  金沢大学, 大学院・医学系研究科, 教授 (40185963)

Co-Investigator(Kenkyū-buntansha) 田端 俊英  金沢大学, 大学院・医学系研究科, 助手 (80303270)
Project Period (FY) 2000 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥60,200,000 (Direct Cost: ¥60,200,000)
Fiscal Year 2004: ¥11,600,000 (Direct Cost: ¥11,600,000)
Fiscal Year 2003: ¥11,900,000 (Direct Cost: ¥11,900,000)
Fiscal Year 2002: ¥11,700,000 (Direct Cost: ¥11,700,000)
Fiscal Year 2001: ¥12,800,000 (Direct Cost: ¥12,800,000)
Fiscal Year 2000: ¥12,200,000 (Direct Cost: ¥12,200,000)
Keywords生後発達 / 小脳 / プルキンエ細胞 / 登上線維 / 多重支配 / シナプス除去 / カルシウム / GABA / カルシウムチャネル / スライス / 培養 / 共培養 / 一酸化窒素 / NO合成酵素
Research Abstract

本研究では、発達期小脳でみられる登上線維シナプス除去と機能成熟の分子機構を解明することを目標とし、種々の自然発生ミュータントマウスおよび遺伝子改変マウスの解析を行ってきた。本年度は、高閾値型のP/Qタイプカルシウムチャネルを形成するα1Aサブユニットのノックアウトマウス(α1A-/-)と、抑制性伝達物質のGABA合成酵素GAD67のノックアウトマウスと野生型マウスとのヘテロマウス(GAD67+/-)を調べた。
生後3〜4週目のα1A-/-では、80%以上のプルキンエ細胞が複数の登上線維による多重支配を受けていることが電気生理学的及び形態学的解析の結果明らかになった。生後1日目からの発達の様子を電気生理学的に詳細に解析した結果、α1A-/-では、生後10日までの過剰な登上線維シナプス除去(前期シナプス除去過程)が著しく障害されていることが判明した。一方、生後10日から16日の間の除去(後期シナプス除去過程)は正常におこった。これから、P/Qタイプカルシウムチャネルを介するプルキンエ細胞へのカルシウム流入が、前期シナプス除去過程に必須であり、後期シナプス除去過程には別の機構が関与することが示唆された。
GAD67+/-では、成熟しても多重登上線維支配を受けるプルキンエ細胞の割合が野生型マウスに比べて明らかに高いという予備的結果を得た。このGAD67+/-の生後1日目からの発達を電気生理学的および形態学的に詳細に解析するとともに、もうひとつのGABA合成酵素であるGAD65のノックアウトマウスを調べ、登上線維シナプス除去と機能成熟に対する抑制性シナプス入力の役割を明らかにするのが今後の課題である。

Report

(5 results)
  • 2004 Annual Research Report
  • 2003 Annual Research Report
  • 2002 Annual Research Report
  • 2001 Annual Research Report
  • 2000 Annual Research Report

Research Products

(67 results)

All 2005 2004 Other

All Journal Article (10 results) Publications (57 results)

  • [Journal Article] Phospholipase Cβ serves as a coincidence detector through its Ca^<2+> dependency for triggering endocannabinoid signal.2005

    • Author(s)
      Hashimotodani, Y.
    • Journal Title

      Neuron 45

      Pages: 257-268

    • Related Report
      2004 Annual Research Report
  • [Journal Article] GABAergic activation of an inwardly rectifying K^+ current in mouse cerebellar Purkinje cells.2005

    • Author(s)
      Tabata, T.
    • Journal Title

      J.Physiol.(London) 563

      Pages: 443-457

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Two distinct classes of muscarinic action on hippocampal inhibitory synapses : M_2-mediated direct suppression and M_1/M_3-mediated indirect suppression through endocannabinoid signaling.2004

    • Author(s)
      Fukudome, Y.
    • Journal Title

      Eur.J.Neurosci. 19

      Pages: 2682-2692

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Distinct roles of Gα_q and Gα_<11> for Purkinje cell signaling and motor behavior.2004

    • Author(s)
      Hartmann, J.
    • Journal Title

      J.Neurosci. 24

      Pages: 5119-5130

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Altered agonist sensitivity and desensitization of neuronal mGluR1 responses in knock-in mice by a single amino acid substitution at the PKC phosphorylaion site.2004

    • Author(s)
      Sato, M.
    • Journal Title

      Eur.J.Neurosci. 20

      Pages: 947-955

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Ca^<2+> activity at GABA_B receptors constitutively promotes metabotropic glutamate signaling in the absence of GABA.2004

    • Author(s)
      Tabata, T.
    • Journal Title

      Proc.Natl.Acad.Sci.USA. 101

      Pages: 16952-16957

    • Related Report
      2004 Annual Research Report
  • [Journal Article] A novel action of stargazin as an enhancer of AMPA receptor activity.2004

    • Author(s)
      Yamazaki, M.
    • Journal Title

      Neurosci.Res. 50

      Pages: 369-374

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Signaling complex formation of phospholipase Cβ4 with mGluR1a and IP3 receptor at the perisynapse and endoplasmic reticulum in the mouse brain.2004

    • Author(s)
      Fukaya, M.
    • Journal Title

      Eur.J.Neurosci. 20

      Pages: 2929-2944

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Retrograde modulation of synaptic transmission mediated by endogenous cannabinoids.2004

    • Author(s)
      Kano, M.
    • Journal Title

      Curr.Neuropharmacol. 2

      Pages: 49-57

    • NAID

      130005447340

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Calcium-dependence of native metabotropic glutamate receptor signaling in central neurons.2004

    • Author(s)
      Tabata, T.
    • Journal Title

      Mol.Neurobiol. 29

      Pages: 261-270

    • Related Report
      2004 Annual Research Report
  • [Publications] Fukudome, Y.: "Insulin-like growth factor-I as a promoting factor for cerebellar Purkinje cell development."Eur.J.Neurosci.. 17. 2006-2016 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Hashimoto, K.: "Functional differentiation of multiple climbing fiber inputs during synapse elimination in the developing cerebellum."Neuron. 38. 785-796 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Ohno-Shosaku, T.: "Postsynaptic M_1 and M_3 receptors are responsible for the muscarinic enhancement of retrograde endocannabinoid signaling in the hippocampus."Eur.J.Neurosci.. 18. 109-116 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Takeda, Y.: "Impaired motor coordination in mice lacking neural recognition molecule NB-3 of the contactin/F3 subgroup."J.Neurobiol.. 56. 252-265 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Kitao, Y.: "ORP15O/HSP12A regulates Purkinje cell survival : A role for ER stress in cerebellar development."J.Neurosci.. 24. 1486-1496 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Miyazaki, T.: "P/Q-type Ca^<2+> channel α1A regulates synaptic competition on developing cerebellar Purkinje cells."J.Neurosci.. 24. 1734-1743 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Kano, M.: "Retrograde modulation of synaptic transmission mediated by endogenous cannabinoids."Curr.Neuropharmacol.. 2. 49-57 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Kano, M.: "Endocannabinoid-mediated modulation of excitatory and inhibitory synaptic transmission. In : EXCITATORY-INHIBITORY BALANCE.(T.K.Hensch, M.Fagiolini, (eds))"Kluwer Academic / Pllenum Publishers, New York/Boston/Dordrecht/London/Moscow. 11 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 橋本浩一: "小脳シナプスの機能発達、可塑性および機能調節におけるグルタミン酸シグナル伝達の役割(脳血管障害による「神経細胞死」の予防と治療)(川合述史/編)"クバプロ. 16 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 狩野方伸: "内因性カンナビノイドによる逆行性シナプス伝達 学術月報"日本学術振興会. 5 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 橋本浩一: "発達期小脳における登上線維シナプスの機能分化 実験医学(御子柴克彦、真鍋俊也、三浦正幸/編)"羊土社. 6 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 橋本浩一: "発達期小脳におけるシナプスの機能分化 蛋白質 核酸 酵素 49 No.3(増刊号/神経回路の機能発現のメカニズム)(大森治紀、渋木克栄、 野田亮、山森哲雄/編)"共立出版. 7 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Kano, M.: "Retrograde signaling at central synapses via endogenous cannabinoids"Mol. Psychiatry. 7. 234-235 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Yoshida, T.: "The cannabinoid CB1 receptor mediates retrograde signals for depolarization-induced suppression of inhibition in cerebellar Purkinje cells"J.Neurosci.. 22. 1690-1697 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Ohno-Shosaku, T.: "Cooperative endocannabinoid production by neuronal depolarization and group I metabotropic glutamate receptor activation"Eur.J.Neurosci.. 15. 953-961 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Nishi, M.: "Motor discoordination in mutant mice lacking junctophilin type 3"Biochem.Biophysic.Res.Comm.. 292. 318-324 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Ohno-Shosaku, T.: "Presynaptic cannabinoid sensitivity is a major determinant of depolarization-induced retrograde suppression at hippocampal synapses"J.Neurosci.. 22. 3864-3872 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Tabata, T.: "Extracellular calcium controls the dynamic range of neuronal metabotropic glutamate receptor responses"Mol.Cell.Neurosci.. 20. 56-68 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Watase, K.: "A long CAG repeat in the mouse Scal locus replicates SCA1 features and reveals the impact of mutant protein solubility on selective neuronal vulnerability"Neuron. 34. 905-919 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Miura, M.: "Group I mtabotropic glutamate receptor signaling via Gαq/Gαll secures the induction of long-term potentiation in the hippocampal area CA1"J.Neurosci.. 22. 8379-8390 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Ichikawa, R.: "Distal extension of climbing fiber territory and multiple innervation caused by aberrant wiring to adjacent spiny branchlets in cerebellar Purkinje cells lacking glutamate receptor GluRδ"J.Neurosci.. 22. 8487-8503 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Kishimoto, Y.: "mGluR1 in cerebellar Purkinje cells is required for normal association of temporally contiguous stimuli in classical conditioning"Eur.J.Neurosci.. 16. 2416-2424 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Kakizawa, S.: "Effects of insulin-like growth factor I on climbing fiber synapse elimination during cerebellar development"Eur.J.Neurosci.. 17. 545-554 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Takeda, Y.: "Impaired motor coordination in mice lacking neural recognition molecule NB-3 of the contactin/F3 subgroup"J.Neurobiol.. (in press).

    • Related Report
      2002 Annual Research Report
  • [Publications] 少作隆子: "グルタミン酸受容体チャネルとシナプス可塑性"医学のあゆみ. 201. 1123-1127 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] 少作隆子: "カンナビノイド受容体(Annual Review 神経 2003)"中外医学社. 7 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] 橋本浩一: "小脳におけるシナプス可塑性 (シリーズ バイオサイエンスの新世紀 11/脳の発生・分化・可塑性)"共立出版 (御子柴克彦、清水孝雄/編). 10 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] T.Ohno-Shosaku: "Endogenous cannabinoids mediate retrograde signals from depolarized postsynaptic neurons to presynaptic terminals"Neuron. 29. 729-738 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] A.W.McGee: "PSD-93 knock-out mice reveal that neuronal MAGUKs are not required for development or function of parallel fiber synapses in cerebellum"J.Neurosci. 21. 3085-3091 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] M.Miyata: "Deficient long-term synaptic depression in the rostral cerebellum correlated with impaired motor learning in phospholipase C β4 mutant mice"Eur.J.Neurosci.. 13. 1945-1954 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] T, Maejima: "Presynaptic in hibition caused by retrograde signal from metabotropic glutamate to cannabinoid receptors"Neuron. 31. 463-475 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] T, Maejima: "Endogenous cannabinoid as a retrograde messenger from depolarized postsynaptic neurons to presynaptic terminals"Neurosci.Res.. 40. 205-210 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] K.Hashimoto: "Roles of glutamate receptor δ2 subunit (GluRδ2) and metabotropic glutamate receptor subtype 1(mGluR1) in climbing fiber synapse elimination during postnatal cerebellar development"J.Neurosci.. 21. 9701-9712 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] K.Hashimoto: "Roles of phospholipase C β4 in synapse elimination and plasticity in developing and mature cerebellum"Mol.Neurobiol.. 23. 69-82 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] T.Tabata: "Heterogeneous intrinsic firing properties of vertebrate retinal ganglion cells"J.Neurophysiol.. 87. 30-41 (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] T.Yoshida: "The cannabinoid CB1 receptor mediates retrograde signals for depolarization-induced suppression of inhibition in cerebellar Purkinje cells"J.Neurosci.. 22. 1690-1697 (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] M.Kano: "Retrograde signaling at central synapses via endogenous cannabinoids"Mol.Psychiatry. 7(in press). (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] T.Ohno-Shosaku: "Cooperative endocannabinoid production by neuronal depolarization and group I metabotropic glutamate receptor activation"Eur. J. Neurosci.. (in press). (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] 橋本浩一: "小脳シナプス可塑性の分子機構"神経研究の進歩. 49. 249-260 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] 橋本浩一: "小脳プルキンエ細胞におけるシナプス可塑性とカルシウム"Clinical Calcium. 11. 1432-1439 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] 少作隆子: "脳内カンナビノイド受容体とシナプス伝達調節"脳の科学. 23. 1000-1002 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] 橋本浩一: "発達脳におけるシナプス除去のメカニズム"医学のあゆみ. 199. 531-534 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] 前島隆司: "カンナビノイド受容体と逆行性シグナル伝達"Clinical Neuroscience. 19. 1431 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Ichise,T.: "mGluR1 in cerebellar Purkinje cells essential for long-term depression, synapse elimination and motor coordination."Science. 288. 1832-1835 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Tsubokawa,H.: "Calcium-dependent persistent facilitation of spike backpropagation in the CA1 pyramidal neurons."J.Neurosci.. 20. 4878-4884 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Kakizawa,S.: "Critical period for activity-dependent synapse elimination in developing cerebellum."J.Neurosci.. 20. 4954-4961 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Furuya,S.: "L-Serine and glycine serve as major astroglia-derived trophic factors for cerebellar Purkinje neurons"Proc.Natl.Acad.Sci.USA.. 97. 11528-11533 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Tabata,T.: "A reliable method for culture of dissociated mouse cerebellar cells enriched for Purkinje Neurons."J.Neurosci.Meth.. 104. 45-53 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Miyata,M.: "Local calcium release in dendritic spines required for long-term synaptic depression."Neuron. 28. 233-244 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Ohno-Shosaku,T.: "Heterosynaptic expression of depolarization-induced suppression of inhibition (DSI) in rat hippocampal cultures."Neurosci.Res.. 36. 67-71 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Kobayashi,K.: "Modest Neuropsychological deficits caused by reduced noradrenaline metabolism in mice heterozygous for a mutated tyrosine hydroxylase gene."J.Neurosci.. 20. 2418-2426 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Tanaka,J.: "Gq protein subunits Gq and G11 are localized at the postsynaptic extra-junctional membrane of cerebellar Purkinje cells and hippocampal pyramidal cells."Eur.J.Neurosci.. 12. 781-792 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Matsuzawa,M.: "Formation of hippocampal synapses on patterned substrates of a laminin-derived synthetic peptide."Eur.J.Neurosci.. 12. 903-910 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Hashimoto,K.: "Climbing fiber synapse elimination during postnatal cerebellar development requires signal transduction involving Gαq and phospholipase Cγ4."Prog.Brain Res.. 124. 31-48 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Ohno-Shosaku,T.: "Endogenous cannabinoids mediate retrograde signals from depolarized postsynaptic neurons to presynaptic terminals."Neuron. 29(in press). (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] Kano,M.: "Endogenous corticotropin-releasing factor (CRF) is required for the induction of cerebellar long-term depression."T.Kato, (ed) Elsevier/Tokyo. 4 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] 柿澤昌: "小脳 脳神経科学イラストレイテッド、第2章 5"羊土社(森寿,真鍋俊也,渡辺雅彦,岡野栄之,宮川剛/編). 6 (2000)

    • Related Report
      2000 Annual Research Report

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Published: 2000-03-31   Modified: 2018-03-28  

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