273
-シン ポジ ウム
S-07-2
Disruption of glia-neuron assemblies in an intractable neurological disorder
Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University
○Jun-ichi Kira
Baló’ s concentric sclerosis (BCS), a variant of multiple sclerosis (MS), is characterized by huge demyelinating lesions with alternating rings of demyelinated and myelin-preserved layers. We found that, despite the presence of numerous glial fibrillary acidic protein (GFAP)-positive astrocytes, there was a marked decrease in the levels of aquaporin-4 (AQP4) and connexin (Cx)43, Cx32 and Cx47 in BCS lesions. At the leading edges, Cx43 and AQP4 were mostly absent despite positive GFAP, Cx32, Cx47, myelin oligodendrocyte glycoprotein, myelin-associated glycoprotein and oligodendrocyte-specific protein immunoreactivity. BCS is thus characterized by extensive loss of Cxs and AQP4, and a lack of autoantibodies to Cxs and AQP4. Similar loss of Cxs and AQP4 without immunoglobulin and complement deposition was also observed in acute lesions in MS cases and in a fraction of neuromyelitis optica (NMO) lesions, although in the latter anti-AQP4 antibody is assumed to destroy astrocytes by a complement-mediated mechanism. Therefore, we propose that autoantibody-independent astrocytopathy is a common denominator for BCS, MS and NMO. As we observed that Th1 cell supernatants containing interferon-gamma decreased expression of Cx43 on astrocytes and reduced Cx43 gap junction functions, T cell-mediated disruption of Cx gap junctions may be critical to disrupt glial assembly.
We found in the active lesions in MS cases that monocarboxylate transporter 4 (MCT4) was diminished in the astrocytic perivascular foot processes, although endothelial monocarboxylate transporter 1 (MCT1) and glucose transporter 1 (GLUT1) were preserved despite massive lymphocytic cuffing. In the active lesions in NMO cases, perivascular MCT4 was also extensively lost, whereas MCT1 and GLUT1 were preserved. Loss of MCT4 in perivascular astrocytic foot processes may cause impaired transport of energy to astrocytes followed by oligodendrocytic and axonal damage in MS and NMO.
《Curriculum Vitae》
Jun-ichi Kira is Professor and Chairman of the Department of Neurology in Neurological institute of the Graduate School of Medical Sciences, Kyushu University, Japan. He graduated with MD in 1979 and completed his PhD in 1986 in Kyushu University. From 1982 to 1985, he went to the Section on Myelin Chemistry, NIH, Bethesda, USA, as a visiting fellow. After coming back from his research in the United States, he became an assistant professor until 1995 and became associate professor until 1997 and he becomes Professor and Chairman of the Department of Neurology. He has served executive committee member of Japanese Society of Neurology, Japanese Society for Neuroimmunology, Japanese Peripheral Nerve Society, and Japan Society of Neurovegetative Research, and Japanese Society of Internal Medicine. He also served chief investigator for the Research Committee of Neuroimmunological Diseases, the Ministry of Health, Labour and Welfare, Japan, from 2002-2008. He is currently a corresponding member of the American Neurological Association, chief editor of Clinical and Experimental Neuroimmunology, and editorial board member of Multiple Sclerosis Journal, Journal of the Neurological Sciences, and Multiple Sclerosis and Related Disorders. Professor Kira’ s current research areas are immunological and genetic studies of multiple sclerosis, clinical and experimental studies of atopic myelitis, and immunobiological studies of neurodegenerative diseases. He has published more than 300 original scientific papers in English journals. He also acts as chief investigator for some clinical trials of disease-modifying drugs against multiple sclerosis in Japan.
S-07-3
Remodeling of Cortical Neuronal Circuits in vivo: Synapse-Microglia Interaction
National Institute for Physiological Science
○Junichi Nabekura，Akiko Miyamoto，
Ryohei Akiyoshi，Hiroaki Wake
[OBJECTIVE] Recent studies have revealed new aspects that microglia constantly and directly survey the synapses in undamaged brain. In the damaged brain, microglial surveillance with contact to neuronal elements, often eliminate the damaged synapses (Wake et al. 2009). Next critical questions to be solved is to elucidate the physiological relevance of microglial prolonged wrapping to neuronal viability.
[Methods] Two photon excitation microscopic observation was applied to the living mice and brain slice preparation to visualize the interaction between cortical neuronal circuits and microglia.
[Result] Epileptic action potentials evoked in pyramidal neurons induced substantial increases in axonal volume, resulting in a sustained and large pathological depolarization. Microglial processes migrated to these swollen axons in a mechanism involving ATP release via volume-activated anion channels. This microglial wrapping of the swollen axon induced a rapid neuronal membrane hyperpolarization, resulting in preventing neuronal death. Thus, we have directly observed that microglia can prevent depolarizing toxicity of axons and neurons by attachment and phagocytosis of damaged neuronal elements.
Besides its elimination of synapses, microglia express various molecules related to synapstogenesis, e.g. BDNF. Indeed, formation of dendritic protrusion was detected following microglia contact onto dendrites at S1 cortex at 8-10 day after birth. Actin was accumulated at the dendritic site at which microglia contacted, and synapse was formed. Injection of minocycline, and the ablation of microglia by selective expression of diphtheria toxin in microglia, both resulted in a decrease in cortical spine density.
[Conclusion] Microglia contacts to neurons contribute the rescue the neuronal damages in pathological brain. In addition, microglia contribute the remodeling of the neuronal circuits in development and damaged brain with formation and elimination synapses.
《Curriculum Vitae》
Professor
1981 School of Medicine, Kyushu University, Fukuoka, Japan (MD) 1981-1983 Internship at Kyushu University Hospital (Obstetrics and Gynecology), 1986 Graduate School of Medical Sciences. Kyushu University (Ph.D) 1986-1989 Research Associate, Washington University, St. Louis USA
1990-1992 Assistant Professor (Neurophysiology), Tohoku University School of Medicine 1992-1994 Associate Professor (Physiology), Akita University School of Medicine 1994-2003 Associate Professor (Physiology), Kyushu University School of Medicine 2003- Professor, Department of Developmental Physiology, NIPS, 2013- Vice Director, NIPS
2013- Senior Program Officer, JSPS
2005-2010 CREST (PI) Japan Science of Technology (JST) 2011-2016 CREST (PI) Japan Science of Technology (JST)
シンポジウム S-07：Disruption of glia-neuron assemblies in intractable neurological disorders
5月19日（木） 8：00～10：00 第7会場(ポートピアホテル本館B1F 偕楽1)
シン ポジ ウム
S-07-2
Disruption of glia-neuron assemblies in an intractable neurological disorder
Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University
○Jun-ichi Kira
Baló’ s concentric sclerosis (BCS), a variant of multiple sclerosis (MS), is characterized by huge demyelinating lesions with alternating rings of demyelinated and myelin-preserved layers. We found that, despite the presence of numerous glial fibrillary acidic protein (GFAP)-positive astrocytes, there was a marked decrease in the levels of aquaporin-4 (AQP4) and connexin (Cx)43, Cx32 and Cx47 in BCS lesions. At the leading edges, Cx43 and AQP4 were mostly absent despite positive GFAP, Cx32, Cx47, myelin oligodendrocyte glycoprotein, myelin-associated glycoprotein and oligodendrocyte-specific protein immunoreactivity. BCS is thus characterized by extensive loss of Cxs and AQP4, and a lack of autoantibodies to Cxs and AQP4. Similar loss of Cxs and AQP4 without immunoglobulin and complement deposition was also observed in acute lesions in MS cases and in a fraction of neuromyelitis optica (NMO) lesions, although in the latter anti-AQP4 antibody is assumed to destroy astrocytes by a complement-mediated mechanism. Therefore, we propose that autoantibody-independent astrocytopathy is a common denominator for BCS, MS and NMO. As we observed that Th1 cell supernatants containing interferon-gamma decreased expression of Cx43 on astrocytes and reduced Cx43 gap junction functions, T cell-mediated disruption of Cx gap junctions may be critical to disrupt glial assembly.
We found in the active lesions in MS cases that monocarboxylate transporter 4 (MCT4) was diminished in the astrocytic perivascular foot processes, although endothelial monocarboxylate transporter 1 (MCT1) and glucose transporter 1 (GLUT1) were preserved despite massive lymphocytic cuffing. In the active lesions in NMO cases, perivascular MCT4 was also extensively lost, whereas MCT1 and GLUT1 were preserved. Loss of MCT4 in perivascular astrocytic foot processes may cause impaired transport of energy to astrocytes followed by oligodendrocytic and axonal damage in MS and NMO.
《Curriculum Vitae》
Jun-ichi Kira is Professor and Chairman of the Department of Neurology in Neurological institute of the Graduate School of Medical Sciences, Kyushu University, Japan. He graduated with MD in 1979 and completed his PhD in 1986 in Kyushu University. From 1982 to 1985, he went to the Section on Myelin Chemistry, NIH, Bethesda, USA, as a visiting fellow. After coming back from his research in the United States, he became an assistant professor until 1995 and became associate professor until 1997 and he becomes Professor and Chairman of the Department of Neurology. He has served executive committee member of Japanese Society of Neurology, Japanese Society for Neuroimmunology, Japanese Peripheral Nerve Society, and Japan Society of Neurovegetative Research, and Japanese Society of Internal Medicine. He also served chief investigator for the Research Committee of Neuroimmunological Diseases, the Ministry of Health, Labour and Welfare, Japan, from 2002-2008. He is currently a corresponding member of the American Neurological Association, chief editor of Clinical and Experimental Neuroimmunology, and editorial board member of Multiple Sclerosis Journal, Journal of the Neurological Sciences, and Multiple Sclerosis and Related Disorders. Professor Kira’ s current research areas are immunological and genetic studies of multiple sclerosis, clinical and experimental studies of atopic myelitis, and immunobiological studies of neurodegenerative diseases. He has published more than 300 original scientific papers in English journals. He also acts as chief investigator for some clinical trials of disease-modifying drugs against multiple sclerosis in Japan.
S-07-3
Remodeling of Cortical Neuronal Circuits in vivo: Synapse-Microglia Interaction
National Institute for Physiological Science
○Junichi Nabekura，Akiko Miyamoto，
Ryohei Akiyoshi，Hiroaki Wake
[OBJECTIVE] Recent studies have revealed new aspects that microglia constantly and directly survey the synapses in undamaged brain. In the damaged brain, microglial surveillance with contact to neuronal elements, often eliminate the damaged synapses (Wake et al. 2009). Next critical questions to be solved is to elucidate the physiological relevance of microglial prolonged wrapping to neuronal viability.
[Methods] Two photon excitation microscopic observation was applied to the living mice and brain slice preparation to visualize the interaction between cortical neuronal circuits and microglia.
[Result] Epileptic action potentials evoked in pyramidal neurons induced substantial increases in axonal volume, resulting in a sustained and large pathological depolarization. Microglial processes migrated to these swollen axons in a mechanism involving ATP release via volume-activated anion channels. This microglial wrapping of the swollen axon induced a rapid neuronal membrane hyperpolarization, resulting in preventing neuronal death. Thus, we have directly observed that microglia can prevent depolarizing toxicity of axons and neurons by attachment and phagocytosis of damaged neuronal elements.
Besides its elimination of synapses, microglia express various molecules related to synapstogenesis, e.g. BDNF. Indeed, formation of dendritic protrusion was detected following microglia contact onto dendrites at S1 cortex at 8-10 day after birth. Actin was accumulated at the dendritic site at which microglia contacted, and synapse was formed. Injection of minocycline, and the ablation of microglia by selective expression of diphtheria toxin in microglia, both resulted in a decrease in cortical spine density.
[Conclusion] Microglia contacts to neurons contribute the rescue the neuronal damages in pathological brain. In addition, microglia contribute the remodeling of the neuronal circuits in development and damaged brain with formation and elimination synapses.
《Curriculum Vitae》
Professor
1981 School of Medicine, Kyushu University, Fukuoka, Japan (MD) 1981-1983 Internship at Kyushu University Hospital (Obstetrics and Gynecology), 1986 Graduate School of Medical Sciences. Kyushu University (Ph.D) 1986-1989 Research Associate, Washington University, St. Louis USA
1990-1992 Assistant Professor (Neurophysiology), Tohoku University School of Medicine 1992-1994 Associate Professor (Physiology), Akita University School of Medicine 1994-2003 Associate Professor (Physiology), Kyushu University School of Medicine 2003- Professor, Department of Developmental Physiology, NIPS, 2013- Vice Director, NIPS
2013- Senior Program Officer, JSPS
2005-2010 CREST (PI) Japan Science of Technology (JST) 2011-2016 CREST (PI) Japan Science of Technology (JST)
シンポジウム S-07：Disruption of glia-neuron assemblies in intractable neurological disorders
5月19日（木） 8：00～10：00 第7会場(ポートピアホテル本館B1F 偕楽1)
274 -シン
ポジ ウム
S-07-4
Emerging roles of microglial cathepsins in intractable neurological disorders
Department of Aging Science and Pharmacology, Faculty of Dental Science, Kyushu University
○Hiroshi Nakanishi
There is increasing evidence that cathepsins (Cat), a group of lysosomal proteases, exert "modulator actions" by which substrates are activated after limited cleavage. We have recently found that microglial CatB, CatS and CatE are linked to the pathogenesis of various intractable neurological disorders through their modulator actions. CatB is responsible for the proteolytic processing of caspase-1, which is known as the interleukin-1β converting enzyme. Caspase-1/CatB system of spinal microglia is involved in inflammatory diseases, such as chronic inflammatory pain.
On the other, CatS of cortical microglia implement distinct morphological and dynamic behaviors of microglial processes, which may in turn drive diurnal variations in dendritic spine density and synaptic strength of cortical neurons. CatS secreted from cortical microglia can proteolytically modulate extracellular matrix molecules (ECM) at synaptic sites. These observations suggest an involvement of microglial ECM/CatS system in mental disorders, such as autism. Finally, CatE can liberate TNF superfamily, number 10 (TNFSF10, previously known as TRAIL) from the surface of microglia, suggesting that TNFSF10/CatE system of microglia plays an important role in immune-mediated inflammatory diseases, such as multiple sclerosis and Alzheimer’s disease. Although medical use of Cat inhibitors is limited, orally-active selective inhibitors of CatB, CatS and CatE may have therapeutic potential for treatment of intractable neurological disorders.
《Curriculum Vitae》
Dr. Hiroshi Nakanishi is currently a Professor of Departmet of Aging Science and Pharmacology, Faculty of Dental Science, Kyushu University. He completed his PhD in Pharmacology, Faculty of Pharmaceutical Sciences, Kyushu University and his post-doctoral training at Department of Anatomy and Neurobiology, the University of Tennessee at Memphis. He became an Associate Professor at Department of Pharmacology in 1999, and a Professor of Laboratory of Oral Aging Science, Faculty of Dental Science, Kyushu University in 2000. He was the Dean of Faculty of Dental Science, Kyushu University from 2011 to 2013. He is now the vice Dean Faculty of Dental Science, Kyushu University from 2014. His reserach is focusing on the physiological and pathological functions of microglia in the central nervous system.
シンポジウム S-07：Disruption of glia-neuron assemblies in intractable neurological disorders
5月19日（木） 8：00～10：00 第7会場(ポートピアホテル本館B1F 偕楽1)
275
-シン ポジ ウム
座長：
村田美穂(国立精神・神経医療研究センター病院 神経 内科)
西川典子(愛媛大学医学部附属病院 薬物療法・神経内科)
≪ねらい≫
社会の変革の中で医師にも多様な働き方，生き方が求めら れるようになってきた．臨床と子育て，介護，基礎研究，ボ ランテイア等々の多様な生き方を，神経学会がシステムとし て支援することは，男女を問わず神経内科医をめざし，また 神経内科医として長く活躍できる人材を確保するために必 須と思われる．本シンポジウムでは多様な勤務体制の一つ としてワークシェアリングを取り上げる．患者，他職種を含 めた職場の同僚に迷惑感をもたれずに，スムーズに神経内科 医のワークシェアリングを推進するためには，まず自らが多 様性の現実を認識することが必須である．その上で実際の 運用のために①業務の効率化（観察，評価，決定の端的な記 載と意志疎通），②時間利用の効率化(在宅勤務を視野に入れ たIT利用)，③リーダーの意識変革が必須といえ，これらに ついて理解を深めるとともに，フロアも含めた積極的な意見 交換の場としたい．
S-08-1
今，なぜワークシェアリングか
国立精神・神経医療研究センター 神経内科
○村田美穂
高齢化社会のなかで，神経内科医の必要性はますます高まっている．
一方で，少子高齢化社会のおいては，子育て・介護は男女を問わず神経 内科医といえども避けては通れない重要な課題である．そのような中 でスキルアップし，社会人としての責任も果たし，かつ神経内科医とし て十分に活躍するためには，ワークシェアリングなどの多様な勤務体 制が不可欠と思われる．欧米にはかなり遅れているものの，わが国で も産業界では大企業を中心にすでに20年以上在宅勤務やワークシェア リングなどが制度として動いている．
しかし，24時間病院にいるからレジデントというのだといわれて，そ うかなと思い，入院受け持ち患者（「私の」患者）は24時間「私が」診た い，という考えで医師として育ってきた我々には，神経内科診療の中で どのようにワークシェアリングをとりいれるのか，スムーズな運用に は超えるべき山がいくつもあると言わざるをえない．しかし，北欧で は大臣もワークシェアリングを実践しており，能力のある者がより能 力を伸ばし，その能力を効率よく人々のために使うためには，超えるべ き山であり，越えられる山である．
神経内科医が多様な勤務体制を取り入れるためにまず不可欠なこと は，3つの信頼，つまり，①患者さんの信頼，②仕事をシェアする同僚医 師の信頼，③医療職を含む職場全体の信頼である．この信頼を得るた めには，自分の得た所見，評価，今後の方針を常に誰にでもわかるよう に記載することが最も重要で，考え方を常にシェアすることはすでに チーム医療の実践のなかで進めてきたことである．さらに，在宅で神 経内科医としての判断，診断等を行うためには，遠隔地医療の診療シス テムが応用可能と思われる．
このようにシステムとしてはすでに実現可能である．これを実際に 運用するために，最も重要なことは，上司の理解，チームリーダー，施 設長の理解であり，これとともに，一人一人が固定観念から逃れて新し い働き方を受け入れることであろう．本シンポジウムを通して，日本 神経学会会員一人一人が，それぞれの立場の神経内科医の能力を100％
生かせるよう，神経内科診療におけるワークシェアリングについて理 解を深め，一歩を踏み出していただければ幸甚である．
《略歴》1984年3月 筑波大学医学専門学群卒業 1984年6月 筑波大学附属病院内科研修医 1986年4月 東京都老人医療センター神経内科医員 1987年4月 筑波大学附属病院神経内科レジデント 1992年3月 筑波大学大学院医学研究科博士課程修了 1992年4月 東京大学医学部附属病院神経内科医員 1993年1月 東京都老人医療センター神経内科医員 1996年4月 東京大学医学部神経内科助手
2004年1月 国立精神・神経センター武蔵病院神経内科医長
2005年3月 国立精神・神経センター武蔵病院第2病棟部（神経内科）部長 2010年4月 国立精神・神経医療研究センター病院 神経内科診療部部長
パーキンソン病・運動障害疾患センター センター長 千葉大学大学院医学研究院客員教授
山梨大学大学院医学研究院客員教授
2012年4月 国立精神・神経医療研究センター病院 特命副院長併任 2016年1月 国立精神・神経医療研究センター病院 副院長 2016年4月 国立精神・神経医療研究センター病院 院長