The role of glia-neuronal lactate shuttle in brain aging

• Project/Area Number: 23650198
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Neurochemistry/Neuropharmacology
• Research Institution: 公益財団法人東京都医学総合研究所 (2012); Tokyo Metropolitan Organization for Medical Research (2011)
• Principal Investigator: SAITOE Minoru 公益財団法人東京都医学総合研究所, 運動・感覚システム研究分野, 参事研究員 (50261839)
• Co-Investigator(Kenkyū-buntansha): HORIUCHI Junjiro 首都大学東京, 理工学研究科, 准教授 (80392364)
• Project Period (FY): 2011 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2012: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2011: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 老化 / 学習記憶 / ショウジョウバエ / ピルビン酸カルボキシラーゼ / D-セリン / (1)学習記憶 / (2)老化 / (3)グリア / (4)乳酸 / (5)ショウジョウバエ

Research Abstract

Age-related memory impairment (AMI) is a debilitating consequence of brain aging and caused by age-related increase in pyruvate carboxylase (PC), a mitochondrial anaplerotic enzyme, in Drosophila. As increase in PC may suppress synthesis of lactate, glia-derived energy source for neurons, in this study, we tried to demonstrate that increase in PC activity inhibits glia-neuron lactate shuttle (GNLS) thereby impairs memory formation. However, our behavioral and biochemical data demonstrated that PC-dependent memory defects are not caused by GNLS inhibition. Although increase in PC activity does not inhibit GNLS, it may inhibit serine racemase (SR) via increasing biosynthesis of its potent inhibitors oxaloacetate (OAA) and aspartate (Asp). SR converts L-serine to D-serine, a glia-derived NMDA receptor agonist. As we expected, D-serine/L-serine ratio is significantly decreased in aged AMI-suffered flies, and this decrease is suppressed by dPC mutations. Furthermore, both AMI and memory defects caused by overexpressing PC in glia are ameliorated by feeding flies D-serine. We propose that age-related increases in glial mitochondrial dPC activity cause AMI by reducing D-serine production.

Research Products

• [Journal Article] 記憶改善に向けた新たな進展:軽度の空腹状態は長期記憶形成を促進する (2013)
  • Author(s): 平野恭敬、齊藤 実
  • Journal Title: 細胞工学 Volume: 32 Pages: 452-453
• [Journal Article] Fasting Launches CRTC to Facilitate Long-term Memory Formation in Drosophila (2013)
  • Author(s): Hirano, Y., Masuda, T., Naganos, S., Matsuno, M., Ueno, K., Miyashita, T., Horiuchi, J., and Saitoe M
  • Journal Title: Science Volume: 339 Pages: 443-446
  • Peer Reviewed
• [Journal Article] Long-term enhancement of synaptic transmission between antennal lobe and mushroom body in cultured Drosophila brain (2013)
  • Author(s): Ueno, K, Naganos, S., Hirano, Y., Horiuchi, J., and Saitoe M
  • Journal Title: J. Physiol Volume: 591 Pages: 287-302
  • Peer Reviewed
• [Journal Article] Perlecan regulates bidirectional Wnt signaling at the Drosophila neuromuscular junction (2013)
  • Author(s): Kamimura K, Ueno K, Nakagawa J, Hamada R, Saitoe M, Maeda N
  • Journal Title: J Cell Biol Volume: 200 Pages: 219-233
  • Peer Reviewed
• [Journal Article] Fasting launches CRTC to facilitate long-term memory formation in Drosophila. (2013)
  • Author(s): Hirano, Y., Masuda, T., Naganos, S., Matsuno, M., Ueno, K., Miyashita, T., Horiuchi, J., Saitoe, M.
  • Journal Title: Science Volume: 339 Issue: 6118 Pages: 443-446
  • DOI: 10.1126/science.1227170
  • Peer Reviewed
• [Journal Article] Long-term enhancement of synaptic transmission between antennal lobe and mushroom body in cultured Drosophila brain. (2013)
  • Author(s): Ueno, K., Naganos, S., Hirano, Y., Horiuchi, J., Saitoe, M.
  • Journal Title: J Physiol. Volume: 591 Issue: 1 Pages: 287-302
  • DOI: 10.1113/jphysiol.2012.242909
  • Peer Reviewed
• [Journal Article] 記憶改善に向けた新たな進展：軽度の空腹状態は長期記憶形成を促進する (2013)
  • Author(s): 平野恭敬
  • Journal Title: 細胞工学 Volume: 32 Pages: 452-453
• [Journal Article] Mg^<2+> block of Drosophila NMDA receptors is required for long-term memory formation and CREB-dependent gene expression (2012)
  • Author(s): Miyashita, T., Oda, Y., Horiuchi, J., Yin, J.C., Morimoto, T., and Saitoe M
  • Journal Title: Neuron Volume: 74 Pages: 887-898
  • Peer Reviewed
• [Journal Article] Mutations in the Drosophila insulin receptor substrate, CHICO, impair olfactory associative learning (2012)
  • Author(s): Naganos, S., Horiuchi, J., and Saitoe, M
  • Journal Title: Neurosci. Res Volume: 73 Pages: 49-55
  • Peer Reviewed
• [Journal Article] Reactive oxygen species are not involved in the onset of age-related memory impairment in Drosophila (2012)
  • Author(s): Hirano, Y., Kuriyama, Y., Miyashita, T., Horiuchi, J., and Saitoe, M
  • Journal Title: Genes, Brain and Behavior Volume: 11 Pages: 79-86
  • Peer Reviewed
• [Journal Article] Mg2+ block of Drosophila NMDA receptors is required for long-term memory formation and CREB-dependent gene expression. (2012)
  • Author(s): Miyashita, T., Oda, Y., Horiuchi, J., Yin, J. C-P., Morimoto, T., Saitoe, M.
  • Journal Title: Neuron Volume: 74 Issue: 5 Pages: 887-898
  • DOI: 10.1016/j.neuron.2012.03.039
  • Peer Reviewed
• [Journal Article] Mg2+ block of Drosophila NMDA receptors is required for long-term memory formation and CREB-dependent gene expression. (2012)
  • Author(s): Miyashita T, Oda Y, Horiuchi J, Yin JC, Morimoto T, Saitoe M.
  • Journal Title: Neuron Volume: in press
  • Peer Reviewed
• [Journal Article] Mutations in the Drosophila insulin receptor substrate, CHICO, impair olfactory associative learning (2012)
  • Author(s): Naganos S, Horiuchi J, Saitoe M
  • Journal Title: Neurosci Res Volume: 73 Issue: 1 Pages: 49-55
  • DOI: 10.1016/j.neures.2012.02.001
  • Peer Reviewed
• [Journal Article] Reactive oxygen species are not involved in the onset of age-related memory impairment in Drosophila (2012)
  • Author(s): Hirano Y, Kuriyama Y, Miyashita T, Horiuchi J, Saitoe M
  • Journal Title: Genes Brain and Behavior Volume: 1 Issue: 1 Pages: 79-86
  • DOI: 10.1111/j.1601-183x.2011.00748.x
  • Peer Reviewed
• [Presentation] The rest interval dependent MAPK activation forms and sustains c-fos and CREB transcriptional cycling required for long-term memory (2012)
  • Author(s): 宮下知之、齊藤 実
  • Organizer: 第35回日本分子生物学会年会ワークショップ「遺伝子発現とタンパク質分解によって産み出される記憶制御のダイナミクス」
  • Place of Presentation: 福岡
  • Year and Date: 2012-12-11
• [Presentation] Long-term enhancement in the mushroom body in cultured Drosophila brain: Cellular substrate for olfactory learning (2012)
  • Author(s): Ueno K, Saitoe M
  • Organizer: International symposium on organization and function of the nervous system
  • Place of Presentation: 東京
  • Year and Date: 2012-11-27
• [Presentation] 神経可塑性に伴うリン酸化プロファイルの網羅的解析 (2012)
  • Author(s): 上野耕平、亀谷富由樹、長谷川成人、齊藤 実
  • Organizer: 日本神経科学大会
  • Place of Presentation: 名古屋
  • Year and Date: 2012-09-20
• [Presentation] ショウジョウバエの神経筋接合部の形成においてパールカンはWntの双方向性シグナルを調節する (2012)
  • Author(s): 神村圭亮、上野耕平、中川 淳、齊藤 実、前田信明
  • Organizer: 日本神経科学大会
  • Place of Presentation: 名古屋
  • Year and Date: 2012-09-20
• [Presentation] 長期記憶形成に必要な神経-グリア相互作用 日本神経科学大会シンポジウム (2012)
  • Author(s): 松野元美、齊藤 実
  • Organizer: 個々の神経細胞の働きを俯瞰して見る脳機能
  • Place of Presentation: 名古屋
  • Year and Date: 2012-09-19
• [Presentation] ショウジョウバエの匂い連合学習で形成される2種類の記憶成分 (2012)
  • Author(s): 長野慎太郎、上野耕平、齊藤 実
  • Organizer: 日本神経科学大会
  • Place of Presentation: 名古屋
  • Year and Date: 2012-09-19
• [Presentation] ショウジョウバエにおいて飢餓は、CREB/CRTC経路の活性化により長期記憶形成を促進する (2012)
  • Author(s): 平野恭敬、齊藤 実、長野慎太郎、松野元美、上野耕平、宮下知之、堀内純二郎
  • Organizer: 日本神経科学大会
  • Place of Presentation: 名古屋
  • Year and Date: 2012-09-18
• [Presentation] 活性型CREBと抑制型CREBの比を調節するメカニズム (2012)
  • Author(s): 宮下知之、齊藤 実
  • Organizer: 日本神経科学大会
  • Place of Presentation: 名古屋
  • Year and Date: 2012-09-18
• [Presentation] Food deprivation facilitates long-term memory formation through activation of the CREB co-activator (2012)
  • Author(s): Hirano Y, Naganos S, Matsuno M, Ueno K, Miyashita T, Horiuchi J, Saitoe M
  • Organizer: CRTC in Drosophila. in Neurofly
  • Place of Presentation: Padua, Italy
  • Year and Date: 2012-09-05
• [Presentation] 食事制限による非特異的な長期記憶促進効果とその分子機構 (2012)
  • Author(s): 齊藤 実、平野恭敬
  • Organizer: 包括脳ワークショップ公開班会議
  • Place of Presentation: 仙台
  • Year and Date: 2012-07-26
• [Presentation] Maintenance of long-term memory requires persistent regulation of gene expression (2011)
  • Author(s): 平野恭敬、齊藤 実
  • Organizer: 第34回日本分子生物学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2011-12-13
• [Presentation] in vivo imaging analysis of neural plasticity in mushroom body neurons. 「Visualization and optic control of neural circuit underlying behavior」 (2011)
  • Author(s): 上野耕平、齊藤 実
  • Organizer: 第34回日本分子生物学会年会ワークショップ
  • Place of Presentation: 横浜
  • Year and Date: 2011-12-13
• [Presentation] ショウジョウバエを用いて何が記憶を作るのかを知り、記憶が出来るところを見る (2011)
  • Author(s): 齊藤 実
  • Organizer: バイオカンファレンス2011
  • Place of Presentation: 東京
  • Year and Date: 2011-11-11
• [Presentation] Learning-related synaptic plasticity in the Drosophila mushroom bodies require correlated activation of NMDA, acetylcholine and dopamine D1 receptors (2011)
  • Author(s): Ueno K, Naganos S, Saitoe M
  • Organizer: in Neurobiology of Drosophila
  • Place of Presentation: Cold Spring Harbor Laboratory, NY, USA
  • Year and Date: 2011-10-06
• [Presentation] Maintenance of long-term memory requires persistent regulation of gene expression (2011)
  • Author(s): Hirano Y, Saitoe M
  • Organizer: in Neurobiology of Drosophila
  • Place of Presentation: Cold Spring Harbor Laboratory, NY, USA
  • Year and Date: 2011-10-04
• [Presentation] 長期記憶の保持には持続的な遺伝子発現制御が必須である (2011)
  • Author(s): 平野恭敬、齊藤 実
  • Organizer: 第34回日本神経科学学会
  • Place of Presentation: 横浜
  • Year and Date: 2011-09-17
• [Presentation] Correlated activation of dopamine receptor is an essential for associative synaptic plasticity relevant to olfactory aversive memory (2011)
  • Author(s): 上野耕平、長野慎太郎、齊藤 実
  • Organizer: 第34回日本神経科学学会
  • Place of Presentation: 横浜
  • Year and Date: 2011-09-15
• [Presentation] Neuron-glia interaction via Drosophila CAM Klingon modulates Repo-mediated glial gene expression required for long-term memory formation (2011)
  • Author(s): 松野元美、齊藤 実
  • Organizer: 第34回日本神経科学学会
  • Place of Presentation: 横浜
  • Year and Date: 2011-09-15
• [Presentation] Regulation of Drosophila age-related memory impairment by glial cells. in Learning and Memory (2011)
  • Author(s): Saitoe M
  • Organizer: A Synthesis of Flies and Honeybees Janelia Farm HHMI Conference
  • Place of Presentation: Janelia Farm Research Campus, VA, USA
  • Year and Date: 2011-05-16
• [Presentation] in vivo imaging analysis of neural plasticity in mushroom body neurons. 「Visualization and optic control of neural circuit underlying behavior」 (2011)
  • Author(s): 上野耕平、齊藤 実
  • Organizer: 第34回日本分子生物学会年会ワークショップ(招待講演)
  • Place of Presentation: 横浜
• [Presentation] Correlated activation of dopamine receptor is an essential for associative synaptic plasticity relevant to olfactory aversive memory. (2011)
  • Author(s): 上野耕平、長野慎太郎、齊藤 実
  • Organizer: 第34回日本神経科学学会
  • Place of Presentation: 横浜
• [Presentation] mediated glial gene expression required for long-term memory formation. (2011)
  • Author(s): 松野元美、齊藤 実
  • Organizer: 第34回日本神経科学学会
  • Place of Presentation: 横浜
• [Presentation] Maintenance of long-term memory requires persistent regulation of gene expression. (2011)
  • Author(s): Hirano Y, Saitoe M.
  • Organizer: Neurobiology of Drosophila.
  • Place of Presentation: Cold Spring Harbor Laboratory, NY, USA
• [Presentation] Learning-related synaptic plasticity in the Drosophila mushroom bodies require correlated activation of NMDA, acetylcholine and dopamine D1 receptors. (2011)
  • Author(s): Ueno K, Naganos S, Saitoe M.
  • Organizer: Neurobiology of Drosophila.
  • Place of Presentation: Cold Spring Harbor Laboratory, NY, USA
• [Presentation] Learning and Memory: A Synthesis of Flies and Honeybees Janelia Farm HHMI Conference. (招待講演) (2001)
  • Author(s): Saitoe M
  • Organizer: Regulation of Drosophila age-related memory impairment by glial cells.(招待講演)
  • Place of Presentation: Janelia Farm Research Campus, VA, USA
• [Presentation] The rest interval dependent MAPK activation forms and sustains c-fos and CREB transcriptional cycling required for long-term memory.
  • Author(s): 齊藤 実
  • Organizer: 第35回日本分子生物学会年会
  • Place of Presentation: 福岡
  • Invited
• [Presentation] 長期記憶形成に必要な神経－グリア相互作用
  • Author(s): 松野元美
  • Organizer: 日本神経科学大会
  • Place of Presentation: 名古屋
  • Invited
• [Remarks] ようこそ東京都医学総合研究所学習記憶プロジェクトHPへ
  • URL: http://www.igakuken.or.jp/memory/