ヒト認知機能を障害させる遺伝子異常を持つモデル動物の作出とその病態解析

2009 Fiscal Year Annual Research Report

• Project/Area Number: 18390316
• Research Institution: Mie University
• Principal Investigator: 岡田 元宏 Mie University, 大学院・医学系研究科, 教授 (10281916)
• Co-Investigator(Kenkyū-buntansha): 兼子 直 弘前大学, 大学院・医学研究科, 教授 (40106852) ; 福澤 雅志 弘前大学, 農学生命科学部, 教授 (10231557)
• Keywords: てんかん / 遺伝子 / 分子生物学 / 神経伝逹

Research Abstract

常染色体優性夜間前頭葉てんかん責任遺伝子S284L変異遺伝子に相同する変異遺伝子を導入した
S284Lトランスジェニックラットは、4週齢で情報伝達機能変異を獲得していたが、てんかん関連性のフェノタイプは認められなかった。6週齢でinterictal dischargeを獲得し、8週齢でictal dischargeを獲得した。また、6週齢では認められなかった、前頭葉(発作焦点領域)の睡眠誘発性グルタミン酸遊離低下がS284L-TGでは認められなかった。以上の結果から、常染色体優性夜間前頭葉てんかんに、中枢性ニコチン性アセチルコリン受容体α4サブユニットの遺伝子変異に伴う、ニコチン性アセチルコリン受容体の機能変異が関与していることを明らかにするとともに、神経伝達機構の発達過程にこのタンパク機能変異が影響を及ぼし、健常システムの機能変異が加わることで、自発性てんかん発作を獲得することが示唆された。
さらに、発症前段階で、機能性疾患の病態成熟を防止できるか否かを検証するために、S284L変異遺伝子に相同するラットS286L変異Chrna4遺伝子にloxP配列を挿入したコンストラクトに、Chrna4遺伝子のプロモーター領域も含めるイントロン領域もクロニーングし、トランスジェニックラット作出用プラスミドを作成を完了した。また、このLoxP配列に選択的なCre発現トランスジェニックラット作出用コンストラクトを組み込んだベクターも完成した。この2種類のベクターをラット受精卵ヘインジェクションし、2種類10系統のトランスジェニックラットの作出が完了した。

Research Products

• [Journal Article] An event-related fNIRS investigation of Japanese word order (2010)
  • Author(s): Nishimura Y, Sugisaki K, Hattori N, Inokuchi Y, Komachi M, Ogawa M, Okada M, Okazaki Y, Taki W, Yamamoto T, Yoshida E, Ayano S
  • Journal Title: Exp Brain Res. (In press)
  • Peer Reviewed
• [Journal Article] Zonisamide enhances delta receptor-associated neurotransmitter release in striato-pallidal pathway (2009)
  • Author(s): Yamamura, S., Ohoyama, K., Naease, H., Okada, M.
  • Journal Title: Neuropharmacology 57 Pages: 322-331
  • Peer Reviewed
• [Journal Article] Effects of quetiapine on monoamine, GABA, and glutamate release in rat prefrontal cortex (2009)
  • Author(s): Yamamura S, Ohoyama K, Hamaguchi T, Kashimoto K, Nakagawa M, Kanehara S, Suzuki D, Matsumoto T, Motomura E, Shiroyama T, Okada M
  • Journal Title: Psychopharmacology 206 Pages: 243-258
  • Peer Reviewed
• [Journal Article] Effects of zotepine on extracellular levels of monoamine, GABA and glutamate in rat prefrontal cortex (2009)
  • Author(s): Yamamura S, Ohoyama K, Hamaguchi T, Nakagawa M, Suzuki D, Matsumoto T, Motomura E, Tanii H, Shiroyama T, Okada M
  • Journal Title: Br J Pharmacol 157 Pages: 656-665
  • Peer Reviewed
• [Journal Article] Knockdown of Cav2.1 calcium channels is sufficient to induce neurological disorders observed in natural occurring Cacnala mutants in mice (2009)
  • Author(s): Saito H, Okada M, Miki T, Wakamori M, Futatsugi A, Mori Y, Mikoshiba K, Suzuki N
  • Journal Title: Biochem Biophys Res Commun 390 Pages: 1029-1033
  • Peer Reviewed
• [Journal Article] Topiramate and zonisamide prevent paradoxical intoxication induced by carbamazepine and phenytoin (2009)
  • Author(s): Yamamura S, Hamaguchi T, Ohoyama K, Sugiura Y, Suzuki D, Kanehara S, Nakagawa M, Motomura E, Matsumoto T, Tanii H, Shiroyama T, Okada M
  • Journal Title: Epilepsy Res 84 Pages: 172-186
  • Peer Reviewed
• [Journal Article] Lack of potassium current in W309R mutant KCNQ3 channel causing benign familial neonatal convulsions (BFNC) (2009)
  • Author(s): Sugiura Y, Nakatsu F, Hiroyasu K, Ishii A, Hirose S, Okada M, Jibiki I, Ohno H, Kaneko S, Ugawa Y
  • Journal Title: Epilepsy Res 84 Pages: 82-85
  • Peer Reviewed
• [Journal Article] Effects of zonisamide on neurotransmitter release associated with inositol triphosphate receptors (2009)
  • Author(s): Yamamura S, Saito H, Suzuki N, Kashimoto S, Hamaguchi T, Ohoyama K, Suzuki D, Kanehara S, Nakagawa M, Shiroyama T, Okada M
  • Journal Title: Neurosci Lett 454 Pages: 91-96
  • Peer Reviewed
• [Journal Article] Asymmetry of prefrontal cortex activities and catechol-O-methyltransferase Val158Met genotype in patients with panic disorder during a verbal fluency task : near-infrared spectroscopy study (2009)
  • Author(s): Tanii H, Nishimura Y, Inoue K, Koshimizu H, Matsumoto R, Takami T, Hara N, Nishida A, Okada M, Kaiya H, Okazaki Y
  • Journal Title: Neurosci Lett 452 Pages: 63-67
  • Peer Reviewed
• [Journal Article] A de novo KCNQ2 mutation detected in non-familial benign neonatal convulsions (2009)
  • Author(s): Ishii A, Fukuma G, Uehara A, Miyajima T, Makita Y, Hamachi A, Yasukochi M, Inoue T, Yasumoto S, Okada M, Kaneko S, Mitsudome A, Hirose S
  • Journal Title: Brain Dev 31 Pages: 27-33
  • Peer Reviewed
• [Journal Article] Intrasubject reproducibility of prefrontal cortex activities during a verbal fluency task over two repeated sessions using multi-channel near-infrared spectroscopy (2009)
  • Author(s): Kakimoto Y, Nishimura Y, Hara N, Okada M, Tanii H, Okazaki Y
  • Journal Title: Psychiatry Clin Neurosci 63 Pages: 491-499
  • Peer Reviewed
• [Journal Article] Relationship between the prefrontal function during a cognitive task and the severity of the symptoms in patients with panic disorder : a multi-channel NIRS study (2009)
  • Author(s): Nishimura Y, Tanii H, Hara N, Inoue K, Kaiya H, Nishida A, Okada M, Okazaki Y
  • Journal Title: Psychiatry Res 172 Pages: 168-172
  • Peer Reviewed
• [Journal Article] Specific panic attack symptoms in panic disorder patients with putative genetic factor (2009)
  • Author(s): Nishimura Y, Tanii H, Hara N, Inoue K, Nishida A, Okada M, Kaiya H, Okazaki Y
  • Journal Title: Psychiatry Clin Neurosci 63 Pages: 251-252
  • Peer Reviewed
• [Journal Article] Overexpression of the signal peptide whirlin isoform 2 is related to disease progression in colorectal cancer patients (2009)
  • Author(s): Toiyama Y, et al.
  • Journal Title: Int J Oncol. 35 Pages: 709-715
  • Peer Reviewed
• [Journal Article] Rac is involved in the interkinetic nuclear migration of cortical progenitor cells (2009)
  • Author(s): Minobe S, et al.
  • Journal Title: Neurosci Res. 63 Pages: 294-301
  • Peer Reviewed
• [Journal Article] Rab11 and its effector Rip11 participate in regulation of insulin granule exocytosis (2009)
  • Author(s): Sugawara K
  • Journal Title: Genes Cells. 14 Pages: 445-456
  • Peer Reviewed
• [Journal Article] Increased susceptibility to spontaneous lung cancer in mice lacking LIM-domain only 7 (2009)
  • Author(s): Genes Cells.
  • Journal Title: Cancer Sci. 100 Pages: 608-616
  • Peer Reviewed