Analysis of sodium pump knockout mice as a pathophysiological model for familial hemiplegic migraine type 2

• Project/Area Number: 26461284
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurology
• Research Institution: Hyogo Medical University
• Principal Investigator: IKEDA KEIKO 兵庫医科大学, 医学部, 教授 (10265241)
• Co-Investigator(Renkei-kenkyūsha): KAWAKAMI KIYOSHI 自治医科大学, 医学部, 教授 (10161283) ; SATAKE SHIN-ICHIRO 自然科学機構, 生理学研究所, 助教 (30360340)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2016: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2015: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000); Fiscal Year 2014: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: ナトリウムポンプ / α2サブユニット / 片頭痛 / 痙攣 / 皮質拡延性抑制 / 電気生理学 / c-Fos / α２サブユニット / 家族性片麻痺性片頭痛 / パッチクランプ法 / 小脳スライス / 病態モデルマウス / 電気生理学実験 / けいれん / ノックアウトマウス / 点突然変異 / トランスジェニックマウス

Outline of Final Research Achievements

The sodium pump α2 subunit is expressed in central nervous tissue, particularly astrocytes and pyramidal cells in the hippocampus. Mutations in ATP1A2 encoding the;sodium pump α2 subunit cause Familial hemiplegic migraine type 2 (FHM2), an autosomal dominant inheritance migraine with aura and motor weakness and in some cases with seizures and cerebellar symptoms. To understand pathophysiology of migraine and develop novel therapeutics and drugs, we examined the Atp1a2 knockout heterozygous mice by histological and electrophysiological analyses. We found that increased sensitivity of induction of CSD (cortical spreading depression) response in the knockout heterozygous mice compared with wild-type littermate mice. We also established the novel transgenic mouse line harboring homologous mutations found in patients. We have examined their sensitivities to seizures and behaviors, and evaluated them as migraine-model mice.

Research Products

• [Journal Article] Effects of a TRPV1 agonist capsaicin on respiratory rhythm generation in brainstem-spinal cord preparation from newborn rats. (2017)
  • Author(s): Tani M, Kotani S, Hayakawa C, Lin ST, Irie S, Ikeda K, Kawakami K, Onimaru H*.
  • Journal Title: Pflugers Arch. Volume: 469(2) Issue: 2 Pages: 327-338
  • DOI: 10.1007/s00424-016-1912-8
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] The respiratory control mechanisms in the brainstem and spinal cord: integrative views of the neuroanatomy and neurophysiology. (2017)
  • Author(s): Ikeda K, Kawakami K, Onimaru H*, Okada Y, Yokota S, Koshiya N, Oku Y, Iizuka M, Koizumi H.
  • Journal Title: J Physiol Sci Volume: 67(1) Issue: 1 Pages: 45-62
  • DOI: 10.1007/s12576-016-0475-y
  • NAID: 40021064542
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] A Novel Reporter Rat Strain That Conditionally Expresses the Bright Red Fluorescent Protein tdTomato. (2016)
  • Author(s): Igarashi H, Koizumi K, Kaneko R, Ikeda K, Egawa R, Yanagawa Y, Muramatsu S, Onimaru H, Ishizuka T, Yawo H.
  • Journal Title: PLoS One. Volume: 11 Issue: 5 Pages: e0155687-e0155687
  • DOI: 10.1371/journal.pone.0155687
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Effects of ouabain on respiratory rhythm generation in brainstem-spinal cord preparation from newborn rats and in decerebrate and arterially perfused in situ preparation from juvenile rats. (2015)
  • Author(s): Tsuzawa K., Yazawa I., Shakuo T., Ikeda K., Kawakami K. and Onimaru H.
  • Journal Title: Neuroscience Volume: 286 Pages: 404-411
  • DOI: 10.1016/j.neuroscience.2014.12.006
  • Peer Reviewed / Open Access
• [Journal Article] A Phox2b BAC Transgenic Rat Line Useful for Understanding Respiratory Rhythm Generator Neural Circuitry. (2015)
  • Author(s): Ikeda K, Takahashi M, Sato S, Igarashi H, Ishizuka T, Yawo H, Arata S, Southard-Smith EM, Kawakami K, Onimaru H.
  • Journal Title: PLoS One Volume: 10 Issue: 7 Pages: 1-23
  • DOI: 10.1371/journal.pone.0132475
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Activation of Six1 Expression in Vertebrate Sensory Neurons. (2015)
  • Author(s): Sato S*, Yajima H, Furuta Y, Ikeda K, Kawakami K.
  • Journal Title: PLoS One Volume: Aug 27;10(8) Issue: 8 Pages: 1-21
  • DOI: 10.1371/journal.pone.0136666
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Long-lasting facilitation of respiratory rhythm by treatment with TRPA1 agonist, cinnamaldehyde (2015)
  • Author(s): M. Tani, I. Yazawa, K. Ikeda, K. Kawakami, H. Onimaru
  • Journal Title: J. Neurophysiology Volume: 114 Issue: 2 Pages: 989-998
  • DOI: 10.1152/jn.00282.2015
  • Peer Reviewed / Open Access
• [Journal Article] Distinct neurological disorders with ATP1A3 mutations. (2014)
  • Author(s): Heinzen, E.L.*, Arzimanoglou, A., Brashear, A., Clapcote, S.J., Gurrieri, F., Goldstein, D.B., Johannesson, S.H., Mikati, M.A., Neville, B., Nicole, S., Ozelius, L.J., Poulsen, H., Schyns, T., Sweadner, K.J., van den Maagdenberg, A., Vilsen, B., the ATP1A3 Working Group (included Ikeda, K.).
  • Journal Title: Lancet Neurol. Volume: 13 Issue: 5 Pages: 503-514
  • DOI: 10.1016/s1474-4422(14)70011-0
  • Peer Reviewed / Open Access
• [Journal Article] Cytoarchitecture and CO2 sensitivity of Phox2b-positive parafacial neurons in the newborn rat medulla. (2014)
  • Author(s): Onimaru H, Ikeda K, Kawakami K
  • Journal Title: Progress in Brain Research Volume: 209 Pages: 57-71
  • DOI: 10.1016/b978-0-444-63274-6.00004-7
  • Peer Reviewed / Open Access
• [Journal Article] Heterozygous mice deficient in Atp1a3 exhibit motor deficits by chronic restraint stress. (2014)
  • Author(s): Sugimoto H, Ikeda K, Kawakami K.
  • Journal Title: Behav Brain Res. Volume: 272 Pages: 100-110
  • DOI: 10.1016/j.bbr.2014.06.048
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Six1 is a key regulator of the developmental and evolutionary architecture of sensory neurons in craniates (2014)
  • Author(s): H. Yajima, M. Suzuki, H. Ochi, K. Ikeda, S. Sato, K. Yamamura, H. Ogino, N. Ueno and K. Kawakami
  • Journal Title: BMC Biol Volume: 12 Issue: 1 Pages: 40-40
  • DOI: 10.1186/1741-7007-12-40
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] 遺伝子改変マウス(Atp1a3+/-)を使った家族性ジストニアパーキンソニズムの病態解明. (2014)
  • Author(s): 池田啓子
  • Journal Title: 加藤記念難病助成基金研究報告集 Volume: 26 Pages: 9-21
  • Acknowledgement Compliant
• [Presentation] Optogenetic analysis of neuronal network of medullary respiratory center in brainstem-spinal cord preparations from transgenic newborn rats expressing Archaerhodopsin in Phox2b positive cells. (2016)
  • Author(s): Onimaru, H., Ikeda, K., Ogawa, M., Ihara, K.-I., Kobayashi, K., Kawakami, K.
  • Organizer: Neuroscience 2016
  • Place of Presentation: San Diego (USA)
  • Year and Date: 2016-11-12
  • Int'l Joint Research
• [Presentation] A novel transgenic rat harboring Phox2b BAC useful for analysis ontogeny of and function of respiratory rhythm generator neuronal complex. (2016)
  • Author(s): Ikeda, K., Onimaru, H., Kawakami, K. : 75th Annual Meeting International Society of Differentiation 19th International Conference, Boston, August 4-8, 2016. (Poster)
  • Organizer: Society for Developmental Biology 75th Annual Meeting International Society of Differentiation 19th International Conference
  • Place of Presentation: Boston (USA)
  • Year and Date: 2016-08-04
  • Int'l Joint Research
• [Presentation] Exploring the neural hyper-active regions in the Sodium pump disease model mice. (2016)
  • Author(s): Ikeda, K., Kawakami, K.
  • Organizer: The 39th Annual Meeting of the Japan Neuroscience Society
  • Place of Presentation: パシフィコ横浜（神奈川県・横浜市）
  • Year and Date: 2016-07-20
  • Int'l Joint Research
• [Presentation] Developmental defect of respiratory center in the medulla of Pax6 mutant rats. (2016)
  • Author(s): Onimaru, H., Lin, S-T., Ikeda, K., Osumi N.
  • Organizer: The 39th Annual Meeting of the Japan Neuroscience Society
  • Place of Presentation: パシフィコ横浜（神奈川県・横浜市）
  • Year and Date: 2016-07-20
  • Int'l Joint Research
• [Presentation] Phox2b遺伝子の発現制御領域下にアーキロドプシンを発現させたトランスジェニックラットにおける延髄呼吸中枢の神経回路の解析. (2016)
  • Author(s): 鬼丸洋、池田啓子、リンスーチン、小川正晃、伊藤寛一郎、小林和人、川上潔
  • Organizer: 第93回日本生理学会大会
  • Place of Presentation: 札幌コンベンションセンター（北海道，札幌）
  • Year and Date: 2016-03-22
• [Presentation] Atp1a3 heterozygous knoch-out mice show reduced social interaction and lower rank in social dominance compared with wild type. (2015)
  • Author(s): Kawakami, K., Sugimoto, H., Ikeda, K.
  • Organizer: 4th Symposium on ATP1A3 in Disease
  • Place of Presentation: Washington (USA)
  • Year and Date: 2015-08-27
  • Int'l Joint Research
• [Presentation] Spontaneous dystonia in Atp1a3+/-. (2015)
  • Author(s): Ikeda, K., Kawakami, K.
  • Organizer: 4th Symposium on ATP1A3 in Disease
  • Place of Presentation: Washington (USA)
  • Year and Date: 2015-08-27
  • Int'l Joint Research
• [Presentation] Atp1a3+/－マウス小脳プルキンエ細胞におけるグルタミン酸輸送体電流の減弱 (2015)
  • Author(s): 佐竹伸一郎、池田啓子、川上 潔、井本敬二
  • Organizer: 第38回 神経科学会
  • Place of Presentation: 神戸
  • Year and Date: 2015-07-28 – 2015-07-31
• [Presentation] Atp1a3+/-マウス小脳プルキンエ細胞におけるグルタミン酸輸送体電流の減弱. (2015)
  • Author(s): 佐竹伸一郎、池田啓子、川上潔、井本敬二
  • Organizer: Neuroscience 2015
  • Place of Presentation: 神戸国際会議場・展示場（兵庫県，神戸）
  • Year and Date: 2015-07-28
• [Presentation] 呼吸中枢神経系解析に有用なトランスジェニックラット. (2015)
  • Author(s): 池田啓子、鬼丸洋、高橋将文、佐藤滋、川上潔
  • Organizer: Neuroscience 2015
  • Place of Presentation: 神戸国際会議場・展示場（兵庫県，神戸）
  • Year and Date: 2015-07-28
• [Presentation] 新生ラット胸髄呼吸性介在ニューロンにおけるグルタミン酸トランスポーターVGLUT1およびVGLUT2の発現. (2015)
  • Author(s): 飯塚眞喜人、池田啓子、鬼丸洋、川上潔、泉﨑雅彦
  • Organizer: Neuroscience 2015
  • Place of Presentation: 神戸国際会議場・展示場（兵庫県，神戸）
  • Year and Date: 2015-07-28
• [Presentation] Flame rat - 赤色蛍光タンパク質(tdTomato)をコンディショナルに発現するトランスジェニックレポーターラットの評価 (2015)
  • Author(s): 五十嵐 敬幸, 小泉 協, 金子 涼輔, 池田 啓子, 鬼丸 洋, 柳川 右千夫, 村松 慎一, 石塚 徹, 八尾 寛
  • Organizer: Neuroscience 2015
  • Place of Presentation: 神戸国際会議場・展示場（兵庫県，神戸）
  • Year and Date: 2015-07-28
• [Presentation] 呼吸リズムを司る神経群pFRGの最近の話題 Ｓ３５ (2015)
  • Author(s): 池田啓子
  • Organizer: 第120回 日本解剖学会総会･全国学術集会，第92回 日本生理学会大会
  • Place of Presentation: 神戸
  • Year and Date: 2015-03-21 – 2015-03-23
• [Presentation] ジストニアモデルマウスとしてのナトリウムポンプα３サブユニット欠損マウス Ｓ60-2 (2015)
  • Author(s): 川上潔、池田啓子
  • Organizer: 第120回 日本解剖学会総会･全国学術集会，第92回 日本生理学会大会
  • Place of Presentation: 神戸
  • Year and Date: 2015-03-21 – 2015-03-23
• [Presentation] 赤色蛍光タンパク質tdTomatoをコンディショナルに発現するレポーターラット．P3-004 (2015)
  • Author(s): 五十嵐敬幸、小泉 協，金子 涼輔， 池田 啓子，鬼丸 洋，柳川 右千夫，村松 慎一，石塚 徹，八尾 寛
  • Organizer: 第120回 日本解剖学会総会･全国学術集会，第92回 日本生理学会大会
  • Place of Presentation: 神戸
  • Year and Date: 2015-03-21 – 2015-03-23
• [Presentation] Recent Advances in Na pump (2015)
  • Author(s): 池田啓子
  • Organizer: 第三回ニューロカンファランス和歌山
  • Place of Presentation: 和歌山
  • Year and Date: 2015-01-11
  • Invited
• [Presentation] TRPA1 agonist, cinnamaldehyde induced long-lasting facilitation of respiratory rhythm in the brainstem-spinal cord preparation isolated from newborn rat and in the in situ perfused - preparation from juvenile rat., 643.27 (2014)
  • Author(s): Onimaru H, Lin S, Tani M, Yazawa I, Ikeda K, Kawakami K.
  • Organizer: Neuroscience2014
  • Place of Presentation: Washington DC, USA
  • Year and Date: 2014-11-15 – 2014-11-19
• [Presentation] Evaluation of a novel reporter rat line which conditionally expresses red fluorescent protein (tdTomato). 657.18 (2014)
  • Author(s): Igrashi H, Koizumi K, Kaneko R, Ikeda K, Onimaru H, Yanagawa Y, Muramatsu S, Ishizuka T, Yawo H.
  • Organizer: Neuroscience2014
  • Place of Presentation: Washington DC, USA
  • Year and Date: 2014-11-15 – 2014-11-19
• [Presentation] Pax6変異ラットの摘出脳幹―脊髄標本における呼吸リズム形成能 P1-195 (2014)
  • Author(s): 鬼丸洋、Lin Shin Tien, 池田啓子、大隅典子
  • Organizer: 第37回 神経科学会
  • Place of Presentation: 横浜（横浜パシフィコ）
  • Year and Date: 2014-09-11 – 2014-09-13
• [Presentation] 赤色蛍光タンパク質tdTomatoをCre-loxPコンディショナルに発現するレポーターラットの評価 P1-383 (2014)
  • Author(s): 五十嵐敬幸、小泉 協，金子 涼輔， 池田 啓子，鬼丸 洋，柳川 右千夫，村松 慎一，石塚 徹，八尾 寛
  • Organizer: 第37回 神経科学会
  • Place of Presentation: 横浜（横浜パシフィコ）
  • Year and Date: 2014-09-11 – 2014-09-13
• [Presentation] Behavioral and electrophysiological analyses of Atp1a3 knockout mice and implication for pathophysiology of dystonia. (Program: p.46) (2014)
  • Author(s): Ikeda K, Chiken S, Nambu A, Sugimoto H, Kawakami K.
  • Organizer: Third symposium ATP1A3 in Disease
  • Place of Presentation: Lunteren,Netherland
  • Year and Date: 2014-08-29 – 2014-08-31
• [Presentation] Altered motor memory in behaviour and electrorphysiological analyses in Atp1a3 heterozygous knockout mice. Third symposium ATP1A3 in Disease. (2014)
  • Author(s): Kawakami K, Satake S, Sugimoto H, Ikeda K.
  • Organizer: Third symposium ATP1A3 in Disease
  • Place of Presentation: Lunteren,Netherland
  • Year and Date: 2014-08-29 – 2014-08-31
• [Presentation] c-Fos expression in epilepsy-prone Atp1a2 and Atp1a3 knockout mouse brains during development. (2014)
  • Author(s): Ikeda, K., Kawakami, K.
  • Organizer: 47th Annual Meeting for the Japanese Society of Developmental Biologists
  • Place of Presentation: Nagoya
  • Year and Date: 2014-05-27 – 2014-05-30