Functional analysis of arcuate nucleus astrocytes with feeding disorders

• Project/Area Number: 17K00918
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Eating habits
• Research Institution: Hamamatsu University School of Medicine
• Principal Investigator: Mutoh Hiroki 浜松医科大学, 医学部, 助教 (60443040)
• Project Period (FY): 2017-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: 摂食障害 / 発育不良 / 神経細胞 / アストロサイト / CaMK2 / 発達異常 / 弓状核 / グリア細胞 / AgRP神経細胞 / POMC神経細胞 / feeding behavior / astrocyte / Ca imaging

Outline of Final Research Achievements

CNPY3 and CaMK2β were identified through genetic analysis of patients with neurological diseases and growth failure, and then their functional analysis was performed by generating the mouse models as a feeding disorder.
CNPY3 KO mice have been found to be a mouse model of disease with growth failure and neurological disorders such as schizophrenia and autism. CNPY3 is further investigated as a novel molecule involved in feeding behaviour, because its expression or function in the brain is completely unknown.
CaMK2β mutation mice are also found to be growth failure. As CaMK2β is specifically expressed in neurons, we are conducting electrophysiological studies to understand how patient mutations in CaMK2β alter the activity of AgRP and POMC neurons that control feeding behaviour.

Academic Significance and Societal Importance of the Research Achievements

摂食障害はメタボリックシンドロームを引き起こすだけでなく、様々な精神疾患を誘発する大きな健康問題である。これまでの研究により、神経細胞やグリア細胞、さらにホルモンなど摂食行動に関わるメカニズムは少しずつ解明されているが、摂食障害・発育不良などを引き起こす詳細な研究、または障害により神経疾患が誘発されるメカニズムは明らかにされていない。
本研究課題において、摂食行動に関与する新規の分子を詳しく機能解析することにより、摂食障害を治療する新たな薬剤開発や治療法につながることが期待される。

Research Products

• [Journal Article] ATP6V0A1 encoding the a1-subunit of the V0 domain of vacuolar H(+)-ATPases is essential for brain development in humans and mice (2021)
  • Author(s): Aoto K, Kato M, Akita T, Nakashima M, Mutoh H, Akasaka N, Tohyama J, Nomura Y, Hoshino K, Ago Y, Tanaka R, Epstein O, Ben-Haim R, Heyman E, Miyazaki T, Belal H, Takabayashi S, Ohba C, Takata A, Mizuguchi T, Miyatake S, Miyake N, Fukuda A, Matsumoto N and Saitsu H
  • Journal Title: Nat Commun Volume: 12 Issue: 1 Pages: 2107-2107
  • DOI: 10.1038/s41467-021-22389-5
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] De novo variants in CAMK2A and CAMK2B cause neurodevelopmental disorders (2018)
  • Author(s): Akita Tenpei、Aoto Kazushi、Kato Mitsuhiro、Shiina Masaaki、Mutoh Hiroki、Nakashima Mitsuko、Kuki Ichiro、Okazaki Shin、Magara Shinichi、Shiihara Takashi、Yokochi Kenji、Aiba Kaori、Tohyama Jun、Ohba Chihiro、Miyatake Satoko、Miyake Noriko、Ogata Kazuhiro、Fukuda Atsuo、Matsumoto Naomichi、Saitsu Hirotomo
  • Journal Title: Annals of Clinical and Translational Neurology Volume: 5 Issue: 3 Pages: 280-296
  • DOI: 10.1002/acn3.528
  • Peer Reviewed / Open Access
• [Journal Article] Biallelic Variants in CNPY3 , Encoding an Endoplasmic Reticulum Chaperone, Cause Early-Onset Epileptic Encephalopathy (2018)
  • Author(s): Mutoh Hiroki、Kato Mitsuhiro、Akita Tenpei、Shibata Takuma、Wakamoto Hiroyuki、Ikeda Hiroko、Kitaura Hiroki、Aoto Kazushi、Nakashima Mitsuko、Wang Tianying、Ohba Chihiro、Miyatake Satoko、Miyake Noriko、Kakita Akiyoshi、Miyake Kensuke、Fukuda Atsuo、Matsumoto Naomichi、Saitsu Hirotomo
  • Journal Title: The American Journal of Human Genetics Volume: 102 Issue: 2 Pages: 321-329
  • DOI: 10.1016/j.ajhg.2018.01.004
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 免疫応答を制御する小胞体シャペロンCNPY3タンパク質異常はWest症候群を引き起こす (2018)
  • Author(s): Mutoh Hiroki
  • Organizer: 日本神経科学大会
  • Int'l Joint Research
• [Presentation] 神経発達障害を引き起こすCaMKIIα/β新生突然変異体はA型電位依存性K電流を増大させる (2018)
  • Author(s): 秋田天平
  • Organizer: 第41回日本神経科学大会
  • Int'l Joint Research
• [Presentation] 神経発達障害を引き起こすCaMKIIα/β新生突然変異体はA型電位依存性K電流を増大させる (2018)
  • Author(s): 秋田天平
  • Organizer: 第95回日本生理学会大会
  • Int'l Joint Research
• [Presentation] WNK3 kinase regulates inwardly rectifying potassium current in layer V pyramidal neurons of the mouse prefrontal cortex (2018)
  • Author(s): Sinha Saran Adya
  • Organizer: 第95回日本生理学会大会
  • Int'l Joint Research
• [Presentation] The role of GABAergic interneuron - astrocyte interaction in epileptic seizures (2018)
  • Author(s): 武藤弘樹
  • Organizer: 第１回山梨大学先端脳科学特別教育プログラム国際シンポジウム
  • Int'l Joint Research
• [Presentation] Regulation of inwardly rectifying potassium current by WNK3 kinase in layer V pyramidal neurons of the mouse prefrontal cortex (2017)
  • Author(s): Sinha Saran Adya
  • Organizer: 第40回日本神経科学大会
  • Int'l Joint Research
• [Presentation] The Role of GABAergic Interneuron-Astrocyte Interaction in Epileptic Seizures (2017)
  • Author(s): 武藤弘樹
  • Organizer: 第40回日本神経科学大会
  • Int'l Joint Research
• [Presentation] てんかん原性獲得過程における抑制性神経とグリア細胞の相互作用 (2017)
  • Author(s): 武藤弘樹
  • Organizer: 第64回中部日本生理学会
• [Book] Optical Probes in Biology (2018)
  • Author(s): Mutoh H, Akemann W, Knopfel T.
  • Total Pages: 511
  • Publisher: CRC Press
  • ISBN: 9781138199934