Kakegawa, Wataru

写真a

Affiliation

School of Medicine, Department of Physiology （Shinanomachi）

Position

Associate Professor

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Career 【 Display / hide 】

  • 2016.07
    -
    Present

    慶應義塾大学, 医学部生理学Ｉ教室, 准教授

  • 2011.10
    -
    2016.06

    慶應義塾大学, 医学部生理学I教室, 専任講師

  • 2007.04
    -
    2011.09

    慶應義塾大学, 医学部生理学I教室, 助教

  • 2004.04
    -
    2007.03

    慶應義塾大学, 医学部生理学I教室, 助手

  • 2003.05
    -
    2003.12

    St. Jude Children's Research Hospital, Department of Developmental Neurobiology, Postdoc

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Academic Background 【 Display / hide 】

  • 1999.04
    -
    2003.03

    Gunma University, 医学系研究科, 生理学

    Graduate School, Completed

  • 1997.04
    -
    1999.03

    Gunma University, 工学系研究科, 材料工学科

    Graduate School, Completed

  • 1993.04
    -
    1997.03

    Gunma University, 工学部, 材料工学科

    University, Graduated

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Academic Degrees 【 Display / hide 】

  • 博士（医学）, Gunma University, Coursework, 2003.03

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Papers 【 Display / hide 】

  • Hyaluronan synthesis supports glutamate transporter activity

    Hayashi M., Nishioka T., Shimizu H., Takahashi K., Kakegawa W., Mikami T., Hirayama Y., Koizumi S., Yoshida S., Yuzaki M., Tammi M., Sekino Y., Kaibuchi K., Shigemoto-Mogami Y., Yasui M., Sato K.

    Journal of Neurochemistry （Journal of Neurochemistry)  150 （ 3 ） 249 - 263 2019.08

    Research paper (scientific journal),  ISSN  00223042

    　View Summary

    © 2019 International Society for Neurochemistry Hyaluronan is synthesized, secreted, and anchored by hyaluronan synthases (HAS) at the plasma membrane and comprises the backbone of perineuronal nets around neuronal soma and dendrites. However, the molecular targets of hyaluronan to regulate synaptic transmission in the central nervous system have not been fully identified. Here, we report that hyaluronan is a negative regulator of excitatory signals. At excitatory synapses, glutamate is removed by glutamate transporters to turn off the signal and prevent excitotoxicity. Hyaluronan synthesized by HAS supports the activity of glial glutamate transporter 1 (GLT1). GLT1 also retracted from cellular processes of cultured astrocytes after hyaluronidase treatment and hyaluronan synthesis inhibition. A serial knockout study showed that all three HAS subtypes recruit GLT1 to cellular processes. Furthermore, hyaluronidase treatment activated neurons in a dissociated rat hippocampal culture and caused neuronal damage due to excitotoxicity. Our findings reveal that hyaluronan helps to turn off excitatory signals by supporting glutamate clearance. (Figure presented.). Cover Image for this issue: doi: 10.1111/jnc.14516.

  • Activity-Dependent Secretion of Synaptic Organizer Cbln1 from Lysosomes in Granule Cell Axons

    Ibata K., Kono M., Narumi S., Motohashi J., Kakegawa W., Kohda K., Yuzaki M.

    Neuron （Neuron)  102 （ 6 ） 1184 - 1198.e10 2019.06

    Research paper (scientific journal),  ISSN  08966273

    　View Summary

    © 2019 Elsevier Inc. Synapse formation is achieved by various synaptic organizers. Although this process is highly regulated by neuronal activity, the underlying molecular mechanisms remain largely unclear. Here we show that Cbln1, a synaptic organizer of the C1q family, is released from lysosomes in axons but not dendrites of cerebellar granule cells in an activity- and Ca2+-dependent manner. Exocytosed Cbln1 was retained on axonal surfaces by binding to its presynaptic receptor neurexin. Cbln1 further diffused laterally along the axonal surface and accumulated at boutons by binding postsynaptic δ2 glutamate receptors. Cbln1 exocytosis was insensitive to tetanus neurotoxin, accompanied by cathepsin B release, and decreased by disrupting lysosomes. Furthermore, overexpression of lysosomal sialidase Neu1 not only inhibited Cbln1 and cathepsin B exocytosis in vitro but also reduced axonal bouton formation in vivo. Our findings imply that co-release of Cbln1 and cathepsin B from lysosomes serves as a new mechanism of activity-dependent coordinated synapse modification. Ibata et al. find that Cbln1 is released from lysosomes by neuronal activity and accumulated at axonal boutons of cerebellar granule cells. Co-release of Cbln1 and lysosomal enzymes may serve as a new mechanism of activity-dependent coordinated synapse modification.

  • Mice lacking EFA6C/Psd2, a guanine nucleotide exchange factor for Arf6, exhibit lower Purkinje cell synaptic density but normal cerebellar motor functions

    Saegusa S., Fukaya M., Kakegawa W., Tanaka M., Katsumata O., Sugawara T., Hara Y., Itakura M., Okubo T., Sato T., Yuzaki M., Sakagami H.

    PLoS ONE （PLoS ONE)  14 （ 5 ）  2019.05

    Research paper (scientific journal)

    　View Summary

    © 2019 Saegusa et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ADP ribosylation factor 6 (Arf6) is a small GTPase that regulates various neuronal events including formation of the axon, dendrites and dendritic spines, and synaptic plasticity through actin cytoskeleton remodeling and endosomal trafficking. EFA6C, also known as Psd2, is a guanine nucleotide exchange factor for Arf6 that is preferentially expressed in the cerebellar cortex of adult mice, particularly in Purkinje cells. However, the roles of EFA6C in cerebellar development and functions remain unknown. In this study, we generated global EFA6C knockout (KO) mice using the CRISPR/Cas9 system and investigated their cerebellar phenotypes by histological and behavioral analyses. Histological analyses revealed that EFA6C KO mice exhibited normal gross anatomy of the cerebellar cortex, in terms of the thickness and cellularity of each layer, morphology of Purkinje cells, and distribution patterns of parallel fibers, climbing fibers, and inhibitory synapses. Electron microscopic observation of the cerebellar molecular layer revealed that the density of asymmetric synapses of Purkinje cells was significantly lower in EFA6C KO mice compared with wild-type control mice. However, behavioral analyses using accelerating rotarod and horizontal optokinetic response tests failed to detect any differences in motor coordination, learning or adaptation between the control and EFA6C KO mice. These results suggest that EFA6C plays ancillary roles in cerebellar development and motor functions.

  • Interneuronal NMDA receptors regulate long-term depression and motor learning in the cerebellum

    Kono M., Kakegawa W., Yoshida K., Yuzaki M.

    Journal of Physiology （Journal of Physiology)  597 （ 3 ） 903 - 920 2019.02

    Research paper (scientific journal), Joint Work,  ISSN  00223751

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    © 2018 The Authors. The Journal of Physiology © 2018 The Physiological Society Key points: NMDA receptors (NMDARs) are required for long-term depression (LTD) at parallel fibre–Purkinje cell synapses, but their cellular localization and physiological functions in vivo are unclear. NMDARs in molecular-layer interneurons (MLIs), but not granule cells or Purkinje cells, are required for LTD, but not long-term potentiation induced by low-frequency stimulation of parallel fibres. Nitric oxide produced by NMDAR activation in MLIs probably mediates LTD induction. NMDARs in granule cells or Purkinje cells are dispensable for motor learning during adaptation of horizontal optokinetic responses. Abstract: Long-term potentiation (LTP) and depression (LTD), which serve as cellular synaptic plasticity models for learning and memory, are crucially regulated by N-methyl-d-aspartate receptors (NMDARs) in various brain regions. In the cerebellum, LTP and LTD at parallel fibre (PF)–Purkinje cell (PC) synapses are thought to mediate certain forms of motor learning. However, while NMDARs are essential for LTD in vitro, their cellular localization remains controversial. In addition, whether and

  • PhotonSABER: new tool shedding light on endocytosis and learning mechanisms in vivo

    Matsuda S., Kakegawa W., Yuzaki M.

    Communicative and Integrative Biology （Communicative and Integrative Biology)  12 （ 1 ） 34 - 37 2019.01

    Research paper (scientific journal)

    　View Summary

    © 2019, © 2019 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. In the central nervous system, activity-dependent endocytosis of postsynaptic AMPA-type glutamate receptors (AMPA receptors) is thought to mediate long-term depression (LTD), which is a synaptic plasticity model in various neuronal circuits. However, whether and how AMPA receptor endocytosis and LTD at specific synapses are causally linked to learning and memory in vivo remains unclear. Recently, we developed a new optogenetic tool, PhotonSABER, which could control AMPA receptor endocytosis in temporal, spatial, and cell-type-specific manners at activated synapses. Using PhotonSABER, we found that AMPA receptor endocytosis and LTD at synapses between parallel fibers and Purkinje cells in the cerebellum mediate oculomotor learning. We also found that PhotonSABER could inhibit endocytosis of epidermal growth factor receptors in HeLa cells upon light stimulation. These results demonstrate that PhotonSABER is a powerful tool for analyzing the physiological functions of endocytosis in non-neuronal cells, as well as the roles of LTD in various brain regions.

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Papers, etc., Registered in KOARA 【 Display / hide 】

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Research Projects of Competitive Funds, etc. 【 Display / hide 】

  • イオンチャネル型グルタミン酸受容体の新規活動様式の解明：KA受容体をモデルとして

    2022.06
    -
    2024.03

    MEXT,JSPS, Grant-in-Aid for Scientific Research, 挑戦的研究（萌芽）, Principal investigator

  • Naked spineから読み解く小脳シナプスの新しい形成・動作原理

    2020.04
    -
    2024.03

    MEXT,JSPS, Grant-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research (B), Principal investigator

  • 新規ケモジェネティクス法による脳内記憶・学習回路の制御と理解

    2020.04
    -
    2022.03

    MEXT,JSPS, Grant-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research on Innovative Areas, Principal investigator

  • 脳内夾雑環境で働く記憶・学習回路の新規化学遺伝学的制御

    2018.04
    -
    2020.03

    MEXT,JSPS, Grant-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research on Innovative Areas, Principal investigator

  • 新規シナプス架橋構造による小脳神経回路形成および運動記憶制御

    2017.04
    -
    2020.03

    MEXT,JSPS, Grant-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research (B), Principal investigator

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Awards 【 Display / hide 】

  • 日本D-アミノ酸学会奨励賞

    KAKEGAWA WATARU, 2014.09, 日本D-アミノ酸学会

    Type of Award： Award from Japanese society, conference, symposium, etc.

  • 入澤宏・彩記念若手奨励賞

    KAKEGAWA WATARU, 2013.03, 日本生理学会

    Type of Award： Award from Japanese society, conference, symposium, etc.

  • The Young Scientists’ Prize of the Commendation for Science and Technology by the Minister of Education, Culture, Sports, Science and Technology

    KAKEGAWA WATARU, 2012.04, 文部科学省, Study of the ionotropic glutamate receptors regulating learning and memory.

    Type of Award： Other

  • 慶應義塾大学医学部三四会奨励賞

    KAKEGAWA WATARU, 2011.11, 慶應義塾大学医学部三四会, D-セリン－グルタミン酸受容体シグナリングによるシナプス可塑性および記憶学習制御

    Type of Award： Other

  • 日本生理学会奨励賞

    KAKEGAWA WATARU, 2008.03, 日本生理学会, シナプス伝達・可塑性を制御するグルタミン酸受容体機能の解明

    Type of Award： Award from Japanese society, conference, symposium, etc.

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Courses Taught 【 Display / hide 】

  • PHYSIOLOGY 2

    2024

  • PHYSIOLOGY 1

    2024

  • PHYSIOLOGY 2

    2023

  • PHYSIOLOGY 1

    2023

  • PHYSIOLOGY 2

    2022

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