Molecular pathophysiology of neurodevelopmental disorders associated with mutations in the genes encoding voltage-gated sodium channels

• Project/Area Number: 25461572
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Nippon Medical School (2015); The Institute of Physical and Chemical Research (2013-2014)
• Principal Investigator: OGIWARA Ikuo 日本医科大学, 医学部, 准教授 (30373286)
• Research Collaborator: MAZAKI Emi 理化学研究所, 脳科学総合研究センター, 技術員
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: トランスレーショナルリサーチ / 知的障害 / てんかん / 自閉症スペクトラム障害 / ナトリウムチャネル遺伝子 / てんかん性脳症 / 興奮性神経細胞 / 抑制性神経細胞 / 脳・神経 / 神経科学

Outline of Final Research Achievements

De novo mutations of the SCN2A encoding a voltage-gated sodium channel Nav1.2 have been associated with epileptic encephalopathy, autism spectrum disorder and intellectual disability. We here found that, in mouse brain, SCN2A was expressed in excitatory neurons and subsets of inhibitory neurons. We also found that mice with a conditional SCN2A deletion in excitatory neurons and those in inhibitory neurons showed normal threshold for seizures induced by chemoconvulsant. We furthermore found that SCN2A knockout mice had deficits in spatial learning and memory, showed enhanced consolidation and decreased extinction of fear-related memory.

Research Products

• [Journal Article] Singular localization of sodium channel β4 subunit in unmyelinated fibres and its role in the striatum. (2014)
  • Author(s): Miyazaki H, Oyama F, Inoue R, Aosaki T, Abe T, Kiyonari H, Kino Y, Kurosawa M, Shimizu J, Ogiwara I, Yamakawa K, Koshimizu Y, Fujiyama F, Kaneko T, Shimizu H, Nagatomo K, Yamada K, Shimogori T, Hattori N, Miura M, Nukina N.
  • Journal Title: Nat Commun. Volume: 5 Issue: 1 Pages: 5525-5525
  • DOI: 10.1038/ncomms6525
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Nav1.1 haploinsufficiency in excitatory neurons ameliorates seizure-associated sudden death in a mouse model of Dravet syndrome. (2013)
  • Author(s): Ogiwara I, Iwasato T, Miyamoto H, Iwata R, Yamagata T, Mazaki E, Yanagawa Y, Tamamaki N, Hensch TK, Itohara S, Yamakawa K.
  • Journal Title: Hum Mol Genet. Volume: 22 Issue: 23 Pages: 4784-4804
  • DOI: 10.1093/hmg/ddt331
  • Peer Reviewed
• [Journal Article] Altered cardiac electrophysiology and SUDEP in a model of Dravet syndrome (2013)
  • Author(s): Auerbach DS, Jones J, Clawson BC, Offord J, Lenk GM, Ogiwara I, Yamakawa K, Meisler MH, Parent JM, Isom LL
  • Journal Title: PLoS One Volume: 8 Issue: 10 Pages: e77843-e77843
  • DOI: 10.1371/journal.pone.0077843
  • Peer Reviewed
• [Presentation] パルブアルブミン陽性細胞特異的SCN1A遺伝子破壊マウスに認められた社会的行動異常と空間記憶学習障害 (2015)
  • Author(s): 荻原郁夫、眞崎恵美、山川和弘
  • Organizer: 第49回日本てんかん学会学術集会
  • Place of Presentation: 長崎県長崎市長崎ブリックホール
  • Year and Date: 2015-10-30
• [Presentation] 線条体無髄投射神経におけるナトリウムチャネルβ4サブユニットの発現解析 (2015)
  • Author(s): 宮崎晴子、小山文隆、井上律子、清成寛、紀嘉浩、黒澤大、荻原郁夫、山川和弘、下郡智美、服部信孝、三浦正巳、貫名信行
  • Organizer: 第38回日本神経科学会大会
  • Place of Presentation: 兵庫県神戸市神戸国際会議場
  • Year and Date: 2015-07-29
• [Presentation] 電位依存性ナトリウムチャネルNav1.2の時空間的発現パターン (2015)
  • Author(s): 立川哲也、荻原郁夫、宮本浩行、山形哲司、眞崎恵美、山川和弘
  • Organizer: 第38回日本神経科学会大会
  • Place of Presentation: 兵庫県神戸市神戸国際会議場
  • Year and Date: 2015-07-29
• [Presentation] Dravet症候群成因解明のためのScn1a遺伝子発現可視化マウスの解析 (2014)
  • Author(s): 荻原郁夫、眞崎恵美、山川和弘
  • Organizer: 第48回日本てんかん学会学術集会
  • Place of Presentation: 京王プラザホテル（新宿）、東京
  • Year and Date: 2014-10-03
• [Presentation] Neuron-type-specific gene deletion reveals a previously unrecognized Nav1.1 distribution in excitatory neurons (2014)
  • Author(s): Ogiwara, I., Iwasato, T., Yamagata, T., Mazaki, E., Yanagawa, Y., Tamamaki, N., Itohara, S., Yamakawa, K.
  • Organizer: 第36回日本神経科学大会
  • Place of Presentation: パシフィコ横浜、横浜
  • Year and Date: 2014-09-12
• [Presentation] 海馬パルブアルブミン抑制性神経細胞におけるNav1.1発現低下がけいれん発作を生じる (2014)
  • Author(s): 荻原郁夫、山川和弘
  • Organizer: 第56回日本小児神経学会総会
  • Place of Presentation: アクトシティ浜松、浜松、静岡
  • Year and Date: 2014-05-30
• [Presentation] パルブアルブミン陽性細胞を標的としたScn1a遺伝子破壊はマウスにてんかん発作と運動失調を引き起こす
  • Author(s): 荻原郁夫、山川和弘
  • Organizer: 第55回日本小児神経学会総会
  • Place of Presentation: 大分県大分市iichiko総合文化センター
• [Presentation] Nav1.1 haploinsufficient excitatory and inhibitory neurons play distinct roles in epilepsy
  • Author(s): Ogiwara I, Iwasato T, Miyamoto H, Iwata R, Yamagata T, Mazaki E, Yanagawa Y, Tamamaki N, Hensch TK, Itohara S, Yamakawa K
  • Organizer: 第36回日本神経科学大会
  • Place of Presentation: 京都府京都市国立京都国際会館
• [Presentation] 抑制性神経細胞のNav1.1ハプロ不全がてんかんの原因で、興奮性神経細胞のNav1.1ハプロ不全は症状を軽減する
  • Author(s): 荻原郁夫、岩里琢治、宮本浩行、岩田亮平、山形哲司、眞崎恵美、柳川右千夫、玉巻伸章、ヘンシュ貴雄、糸原重美、山川和弘
  • Organizer: 第47回日本てんかん学会学術集会
  • Place of Presentation: 福岡県北九州市北九州国際会議場
• [Presentation] Nav1.1 haploinsufficient excitatory and inhibitory neurons play distinct roles in the epileptic pathology in Dravet syndrome model mice
  • Author(s): Ogiwara I, Iwasato T, Miyamoto H, Iwata R, Yamagata T, Mazaki E, Yanagawa Y, Tamamaki N, Hensch TK, Itohara S, Yamakawa
  • Organizer: Neuroscience 2013
  • Place of Presentation: San Diego Convention Center, San Diego, CA, USA
• [Presentation] SCN1A遺伝子の抑制性細胞特異的ノックアウトは高致死性てんかんを生じるが、興奮性細胞特異的ノックアウトで生存率が上昇する
  • Author(s): 荻原郁夫、岩里琢治、宮本浩行、岩田亮平、山形哲司、眞崎恵美、柳川右千夫、玉巻伸章、ヘンシュ貴雄、糸原重美、山川和弘
  • Organizer: 日本人類遺伝学会第58回大会
  • Place of Presentation: 宮城県仙台市江陽グランドホテル
• [Presentation] Heart rate variability analysis reveals altered autonomic tone in a mouse model of Dravet syndrome
  • Author(s): Auerbach DS, Clawson BC, Ogiwara I, Yamakawa K, Meisler MH, Parent JM, Isom LL
  • Organizer: American Epilepsy Society 67th annual meeting
  • Place of Presentation: Walter E. Washington Convention Center, Washington DC, USA
• [Remarks] 理化学研究所神経遺伝研究チームホームページ
  • URL: http://www.brain.riken.go.jp/labs/ngs/indexj.html
• [Remarks] 理研プレスリリース
  • URL: http://www.riken.jp/pr/press/2013/20130807_1/