BRAIN and NERVE－神経研究の進歩70巻7号

2018年07月発行

増大特集 記憶と忘却に関わる脳のしくみ—分子機構から健忘の症候まで

記憶・学習の分子機構—そのときシナプスでは何が起きているのか

著者： 掛川渉¹ 柚﨑通介¹

所属機関： ¹慶應義塾大学医学部生理学教室

ページ範囲：P.677 - P.687

文献概要

脳内の神経細胞をつなぐシナプスは，記憶・学習を支える重要な構造である。近年，シナプスは経験や環境に応じて絶えずその形態や機能を変化させることがわかってきた。中でも，運動系を制御する小脳は，一生涯を通じて観察されるダイナミックなシナプス改変を介して運動記憶・学習に寄与する。今日，デルタ受容体やC1qファミリー分子をはじめ，シナプス機能や記憶・学習に関わるさまざまな分子たちの挙動が明らかにされつつある。

参考文献

1)Squire LR, Zola SM: Structure and function of declarative and nondeclarative memory systems. Proc Natl Acad Sci U S A 93: 13515-13522, 1996

2)Martin SJ, Grimwood PD, Morris RG: Synaptic plasticity and memory: an evaluation of the hypothesis. Annu Rev Neurosci 23: 649-711, 2000

3)辻省次（総編集）, 西澤正豊（専門編集）: 小脳と運動失調: 小脳はなにをしているのか. 中山書店, 東京, 2013

4)De Zeeuw CI, Ten Brinke, MM: Motor learning and the cerebellum. Cold Spring Harb Perspect Biol 7: a021683, 2015［doi: 10.1101/cshperspect.a021683］

5)Ito M, Yamaguchi K, Nagao S, Yamazaki T: Long-term depression as a model of cerebellar plasticity. Prog Brain Res 210: 1-30, 2014

6)Altman J, Bayer SA: Development of the Cerebellar System: In Relation to Its Evolution, Structure, and Functions. CRC Press,Boca Raton, 1997

7)Shephred GM (ed) The Synaptic Organization of the Brain, Fifth Edition. Oxford University Press, New York, 2004

-permeable AMPA receptors in Bergmann glia. Science 292: 926-929, 2001

9)Yuzaki M: Synapse formation and maintenance by C1q family proteins: a new class of secreted synapse organizers. Eur J Neurosci 32: 191-197, 2010

10)Yuzaki M: Two classes of secreted synaptic organizers in the central nervous system. Annu Rev Physiol 80: 243-262, 2018

11)Matsuda K, Miura E, Miyazaki T, Kakegawa W, Emi K, et al: Cbln1 is a ligand for an orphan glutamate receptor δ2, a bidirectional synapse organizer. Science 328: 363-368, 2010

12)Iijima T, Miura E, Watanabe M, Yuzaki M: Distinct expression of C1q-like family mRNAs in mouse brain and biochemical characterization of their encoded proteins. Eur J Neurosci 31: 1606-1615, 2010

13)Miura E, Iijima T, Yuzaki M, Watanabe M: Distinct expression of Cbln family mRNAs in developing and adult mouse brains. Eur J Neurosci 24: 750-760, 2006

14)Hirai H, Pang Z, Bao D, Miyazaki T, Li L, et al: Cbln1 is essential for synaptic integrity and plasticity in the cerebellum. Nat Neurosci 8: 1534-1541, 2005

15)Kashiwabuchi N, Ikeda K, Araki K, Hirano T, Shibuki K, et al: Impairment of motor coordination, Purkinje cell synapse formation, and cerebellar long-term depression in GluRδ2 mutant mice. Cell 81: 245-252, 1995

16)Araki K, Meguro H, Kushiya E, Takayama C, Inoue Y, et al: Selective expression of the glutamate receptor channel δ2 subunit in cerebellar Purkinje cells. Biochem Biophys Res Commun 197: 1267-1276, 1993

17)Lomeli H, Sprengel R, Laurie DJ, Köhr G, Herb A, et al: The rat δ-1 and δ-2 subunits extend the excitatory amino acid receptor family. FEBS Lett 315: 318-322, 1993

18)Yuzaki M: The δ2 glutamate receptor: 10 years later. Neurosci Res 46: 11-22, 2003

19)Yuzaki M, Aricescu AR: A GluD coming-of-age story. Trends Neurosci 40: 138-150, 2017

20)Ito-Ishida A, Miura E, Emi K, Matsuda K, Iijima T, et al: Cbln1 regulates rapid formation and maintenance of excitatory synapses in mature cerebellar Purkinje cells in vitro and in vivo. J Neurosci 28: 5920-5930, 2008

21)Matsuda K, Yuzaki M: Cbln family proteins promote synapse formation by regulating distinct neurexin signaling pathways in various brain regions. Eur J Neurosci 33: 1447-1461, 2011

22)Elegheert J, Kakegawa W, Clay JE, Shanks NF, Behiels E, et al: Structural basis for integration of GluD receptors within synaptic organizer complexes. Science 353: 295-299, 2016

23)Uemura T, Lee SJ, Yasumura M, Takeuchi T, Yoshida T, et al: Trans-synaptic interaction of GluRδ2 and Neurexin through Cbln1 mediates synapse formation in the cerebellum. Cell 141: 1068-1079, 2010

24)Watanabe M, Kano M: Climbing fiber synapse elimination in cerebellar Purkinje cells. Eur J Neurosci 34: 1697-1710, 2011

25)渡邉貴樹, 上阪直史, 狩野方伸: 生後発達期の小脳におけるシナプス刈り込みのメカニズム. 生化学88: 621-629, 2016

26)Kakegawa W, Mitakidis N, Miura E, Abe M, Matsuda K, et al: Anterograde C1ql1 signaling is required in order to determine and maintain a single-winner climbing fiber in the mouse cerebellum. Neuron 85: 316-329, 2015

27)Uesaka N, Uchigashima M, Mikuni T, Nakazawa T, Nakao H, et al: Retrograde semaphorin signaling regulates synapse elimination in the developing mouse brain. Science 344: 1020-1023, 2014

28)Uesaka N, Abe M, Konno K, Yamazaki M, Sakoori K, et al: Retrograde signaling from progranulin to sort1 counteracts synapse elimination in the developing cerebellum. Neuron 97: 796-805 e795, 2018［doi: 10.1016/j.neuron.2018.01.018］

29)Albus JS: A theory of cerebellar function. Math Biosci 10: 25-61, 1971

30)Marr D: A theory of cerebellar cortex. J Physiol 202: 437-470, 1969

31)Yuzaki M: Cerebellar LTD vs. motor learning-lessons learned from studying GluD2. Neural Netw 47: 36-41, 2013

32)Kohda K, Kakegawa W, Matsuda S, Yamamoto T, Hirano H, et al: The δ2 glutamate receptor gates long-term depression by coordinating interactions between two AMPA receptor phosphorylation sites. Proc Natl Acad Sci U S A 110: E948-E957, 2013［doi: 10.1073/pnas.1218380110］

33)Hironaka K, Umemori H, Tezuka T, Mishina M, Yamamoto T: The protein-tyrosine phosphatase PTPMEG interacts with glutamate receptor δ2 and epsilon subunits. J Biol Chem 275: 16167-16173, 2000

34)Naur P, Hansen KB, Kristensen AS, Dravid SM, Pickering DS, et al: Ionotropic glutamate-like receptor δ2 binds D-serine and glycine. Proc Natl Acad Sci U S A 104: 14116-14121, 2007

35)Kakegawa W, Miyoshi Y, Hamase K, Matsuda S, Matsuda K, et al: D-Serine regulates cerebellar LTD and motor coordination through the δ2 glutamate receptor. Nat Neurosci 14: 603-611, 2011

36)Emi K, Kakegawa W, Miura E, Ito-Ishida A, Kohda K, et al: Reevaluation of the role of parallel fiber synapses in delay eyeblink conditioning in mice using Cbln1 as a tool. Front Neural Circuits 7: 180, 2013［doi: 10.3389/fncir.2013.00180］

37)Gallimore AR, Aricescu AR, Yuzaki M, Calinescu R: A computational model for the AMPA receptor phosphorylation master switch regulating cerebellar long-term depression. PLoS Comput Biol 12: e1004664, 2016［doi: 10.1371/journal.pcbi.1004664］

38)Schonewille M, Gao Z, Boele HJ, Veloz MF, Amerika WE, et al: Reevaluating the role of LTD in cerebellar motor learning. Neuron 70: 43-50, 2011

39)Gutierrez-Castellanos N, Da Silva-Matos CM, Zhou K, Canto CB, Renner MC, et al: Motor learning requires purkinje cell synaptic potentiation through activation of AMPA-receptor subunit GluA3. Neuron 93: 409-424, 2017

40)Schonewille M, Belmeguenai A, Koekkoek SK, Houtman SH, Boele HJ, et al: Purkinje cell-specific knockout of the protein phosphatase PP2B impairs potentiation and cerebellar motor learning. Neuron 67: 618-628, 2010

41)Konno K, Matsuda K, Nakamoto C, Uchigashima M, Miyazaki T, et al: Enriched expression of GluD1 in higher brain regions and its involvement in parallel fiber-interneuron synapse formation in the cerebellum. J Neurosci 34: 7412-7424, 2014