Metabotropic glutamate receptor gates LTP induction in hippocampus

• Project/Area Number: 21500303
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Neuroscience in general
• Research Institution: Jikei University School of Medicine
• Principal Investigator: WATABE Ayako m. 東京慈恵会医科大学, 医学部, 講師 (00334277)
• Project Period (FY): 2009 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2011: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2010: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2009: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 脳・神経 / 可塑性 / 代謝型受容体 / NMDA受容体 / VDCC / 代謝型グルタミン酸受容体 / 電位依存性カルシウムチャネル / NMDA型グルタミン酸受容体 / 長期増強 / 細胞内カルシウムストア / 海馬

Research Abstract

Long-term potentiation(LTP) of synaptic transmission has been regarded as the neuronal basis underlying memory formation. In the CA1 region of the hippocampus, LTP induction has been supposed to require the coincident activation of pre-and postsynaptic neurons, as described in Hebbian hypothesis. Since the Ca^<2+> influx through N-methyl-D-aspartate receptors(NMDARs) plays a crucial role in the induction of LTP, NMDARs, with their characteristics as a coincident detector, are widely accepted as the molecular basis of Hebbian LTP. In contrast, the role of Ca^<2+> influx through voltage-dependent calcium channels(VDCCs) has not been fully addressed yet. Here, we found that LTP can be induced by postsynaptic repetitive depolarization alone in the absence of presynaptic inputs, which was dependent on VDCCs instead of NMDARs, and this form of LTP was non-Hebbian neuron-wide nature.
Also, while the metabotropic glutamate receptor(mGluR) is supposed to modulate VDCCs, its role in LTP has not been well characterized yet. By using subtype-specific knockout mice, we found that mGluR5 induces facilitation of the depolarization-evoked calcium current, which is dependent on the activation of calcium-induced calcium release(CICR) triggered by VDCC. We also showed that mGluR5 enhanced VDCC-dependent LTP of synaptic transmission. We found that L-type VDCCs andmGluR5 form a complex by coimmunoprecipitation, suggesting that the specific functional coupling between mGluR5, InsP_3 receptors(InsP_3Rs) and L-VDCCs played a pivotal role in the calcium-current facilitation.
Taken together, the present study has identified a novel mechanism of the interaction between the mGluR and calcium signaling, and suggested contribution of mGluR5 to neuron-wide non-Hebbian plasticity which works in concert with synapse-specific Hebbian plasticity to help information processing in memory formation.

Research Products

• [Journal Article] Dysfunction of the RAR/RXR signaling pathway in the forebrain impairs hippocampal memory and synaptic plasticity (2012)
  • Author(s): Nomoto, M., Takeda, Y., Uchida, S., Mitsuda, K., Enomoto, H., Saitoh, K., Watabe, A. M., Kobayashi, S, Masushige, S., Manabe, T., Satoshi Kida. S
  • Journal Title: Molecular Brain Volume: 5(8)
• [Journal Article] Functional coupling of the metabotropic glutamate receptor, InsP3 receptor and L-type Ca2+ channel in mouse CA1 pyramidal cells (2012)
  • Author(s): Kato, H., Kassai, H., Watabe, A.M., Aiba, A., Manabe, T.
  • Journal Title: J.Physiol. Volume: (in press)
  • Peer Reviewed
• [Journal Article] Dysfunction of the RAR/RXR signaling pathway in the forebrain impairs hippocampal memory and synaptic plasticity (2012)
  • Author(s): Nomoto, M., Takeda, Y., Uchida, S., Mitsuda, K., Enomoto, H., Saitoh, K., Watabe, A.M., Kobayashi, S.Masushige, S., Manabe, T., Satoshi Kida, S.
  • Journal Title: Molecular Brain Volume: 5
  • Peer Reviewed
• [Journal Article] The mechanisms of the strong inhibitory modulation of long-term potentiation in the rat dentate gyrus (2011)
  • Author(s): Arima-Yoshida, F., Watabe, A. M., Manabe, T
  • Journal Title: Eur J Neurosci Volume: 33(9) Pages: 1637-46
• [Journal Article] β-Adrenergic Receptor Activation Rescues Theta Frequency Stimulation-Induced LTP Deficits in Mice Expressing C-Terminally Truncated NMDA Receptor GluN2A Subunits (2011)
  • Author(s): Moody, T., Watabe, A. M., Indersmitten, T., Noboru H. Komiyama, N. H., Grant, S. G. N., and Thomas J. O' Dell, T. J
  • Journal Title: Learning and Memory Volume: 18 Pages: 118-127
• [Journal Article] The mechanisms of the strong inhibitory modulation of long-term potentiation in the rat dentate gyrus (2011)
  • Author(s): Arima-Yoshida, F., Watabe, A.M., Manabe, T.
  • Journal Title: Eur J Neurosci Volume: 33 Pages: 1637-46
  • Peer Reviewed
• [Journal Article] beta-Adrenergic Receptor Activation Rescues Theta Frequency Stimulation-Induced LTP Deficits in Mice Expressing C-Terminally Truncated NMDA Receptor GluN2A Subunits (2011)
  • Author(s): Moody, T., Watabe, A.M., Indersmitten, T., Noboru H.Komiyama, N.H., Grant, S.G.N., Thomas, J.O.Del, T.J.
  • Journal Title: Learning and Memory Volume: 18 Pages: 118-127
  • Peer Reviewed
• [Journal Article] β-Adrenergic Receptor Activation Rescues Theta Frequency Stimulation-Induced LTP Deficits in Mice Expressing C-Terminally Truncated NMDA Receptor GluN2A Subunits. (2011)
  • Author(s): Moody, T., Watabe, A.M., Indersmitten, T., Noboru H.Komiyama, N.H., Grant, S.G.N., Thomas J.O'Dell, T.J.
  • Journal Title: Learning and Memory Volume: 18 Pages: 118-127
  • Peer Reviewed
• [Journal Article] Distinct target cell-dependent forms of short-term plasticity of the central visceral afferent synapses of the rat (2010)
  • Author(s): Yamamoto K., Noguchi J., Yamada C., Watabe, A. M., and Kato F
  • Journal Title: BMC Neuroscience Volume: 11 Pages: 134-134
• [Journal Article] Distinct target cell-dependent forms of short-term plasticity of the central visceral afferent synapses of the rat. (2010)
  • Author(s): Yamamoto, K., Noguchi, J., Yamada, C., Watabe, A.M., Kato, F.
  • Journal Title: BMC Neuroscience Volume: 11 Pages: 1-18
  • Peer Reviewed
• [Journal Article] Involvement of NMDAR2A tyrosine phosphorylation in depression-related behavior (2009)
  • Author(s): Taniguchi, S., Nakazawa, T., Tanimura, A., Kiyama, Y., Tezuka, T., Watabe, A. M., Katayama, N., Yokoyama, K., Inoue, T., Izumi-Nakaseko, H., Kakuta, S., Sudo, K., Iwakura, Y., Umemori, H., Inoue, T., Murphy, N. P., Hashimoto, K., Kano, M., Manabe, T., and
  • Journal Title: EMBO J Volume: 28(23) Pages: 3717-29
• [Journal Article] Non-Hebbian synaptic plasticity induced by repetitive postsynaptic action potentials (2009)
  • Author(s): Kato, K. K., Watabe, A. M., and Manabe, T
  • Journal Title: J. Neurosci Volume: 29 Pages: 11153-11160
• [Journal Article] Involvement of NMDAR2A tyrosine phosphorylation in depression-related behavior. (2009)
  • Author(s): Taniguchi, S., Nakazawa.T., Tanimura.A., Kiyama, Y., Tezuka.T., Watabe.A.M., Katayama.N., Yokoyama.K., Inoue, T., Izumi-Nakaseko.H., Kakuta.S., Sudo, K., Iwakura.Y., Umemori.H., Inoue, T., Murphy, N.P., Hashimoto.K., Kano, M., Manabe.T., Yamamoto.T.
  • Journal Title: EMBO J. 28 Pages: 3717-3729
  • Peer Reviewed
• [Journal Article] Non-Hebbian synaptic plasticity induced by repetitive postsynapticaction potentials. (2009)
  • Author(s): Kato, K.K., Watabe, A.M., Manabe, T.
  • Journal Title: J. Neurosci. 29 Pages: 11153-11160
  • Peer Reviewed
• [Journal Article] Functional coupling of the metabotropic glutamate receptor, InsP3 receptor and L-type Ca2+channel in mouse CA1 pyramidal cells
  • Author(s): Kato, H., Kassai, H., Watabe, A. M., Aiba, A., and Manabe, T
  • Journal Title: J. Physiol Volume: (In press)
• [Presentation] 神経障害性疼痛を示す糖尿病マウスにおける扁桃体シナプス伝達増強Potentiated synaptic transmission in the nociceptive amygdala of diabetic mice with neuropathic pain (2012)
  • Author(s): Ochiai, T., Takahashi, Y., Asato, M., Watabe, A. M., Ohsawa, M., Kamei, J., Kato, F
  • Organizer: 第85回日本薬理学会
  • Place of Presentation: 京都
• [Presentation] 神経障害性疼痛を示す糖尿病マウスにおける扁桃体シナプス伝達増強Potentiated synaptic transmission in the nociceptive amygdala of diabetic mice with neuropathic pain (2012)
  • Author(s): Ochiai, T., Takahashi, Y., Asato, M., Watabe, A.M., Ohsawa, M., Kamei, J., Kato, F.
  • Organizer: 第85回日本薬理学会
  • Place of Presentation: 京都府京都市
• [Presentation] Maintenance of synaptic transmission depends on lactate transport through mo nocarboxylate transporter (2011)
  • Author(s): Nagase, M., Watabe, A. M., Kato, F
  • Organizer: 第88回日本生理学会大会
  • Year and Date: 2011-03-28
• [Presentation] Potentiated synaptic transmission in the nociceptive amygdala of diabetic mice with neuropathic pain behaviors (2011)
  • Author(s): Ochiai, T., Takahashi, Y., Asato, M., Watabe, A. M., Ohsawa, M., Kamei, J., Kato, F
  • Organizer: 第88回日本生理学会
  • Year and Date: 2011-03-28
• [Presentation] Presynaptic mechanisms underlie synaptic potentiation in the nociceptive amygdala in diabetes-linked neuropathic pain (2011)
  • Author(s): Ochiai, T., Takahashi, Y., Asato, M., Watabe, A. M., Ohsawa, M., Kamei, J., Kato, F
  • Organizer: 41st Annual meeting for the Society for Neuroscience
  • Place of Presentation: Washington DC
• [Presentation] Maintenance of synaptic transmission depends more on monocarboxylate transport at a higher frequency (2011)
  • Author(s): Nagase, M., Watabe, A. M., Kato, F
  • Organizer: 41st Annual meeting for the Society for Neuroscience
  • Place of Presentation: Washington DC
• [Presentation] 胎生～新生期における化学暴露が扁桃体神経興奮性に及ぼす影響の多面的評価法Multiple parameter evaluation of the altered neuronal excitability in the central amygdala of the rats with perinatal administration of ethanol, nicotine and valproate (2011)
  • Author(s): 高橋由香里、永瀬将志、落合敏平、安井豊、中尾彩乃、渡部文子、高木聡、佐藤優、奥津裕也、守口徹、佐藤薫、加藤総夫
  • Organizer: 第34回日本神経科学会大会
  • Place of Presentation: 横浜
• [Presentation] シナプス伝達維持におけるモノカルボン酸トランスポーター依存性エネルギーの役割Synapse type-dependent contributions of MCT-dependent energy supply to the maintenance of transmission in the rat brain (2011)
  • Author(s): Nagase, M., Watabe, A. M., Kato, F
  • Organizer: 第34回日本神経科学会大会
  • Place of Presentation: 横浜
• [Presentation] 神経障害性疼痛を伴う糖尿病マウスにおける侵害受容性扁桃体のシナプス伝達増強Potentiated synaptic transmission in the nociceptive amygdala of diabetic mice with neuropathic pain (2011)
  • Author(s): Ochiai, T., Takahashi, Y., Asato, M., Watabe, A. M., Ohsawa, M., Kamei, J., Kato, F
  • Organizer: 第34回日本神経科学会大会
  • Place of Presentation: 横浜
• [Presentation] 胎生～新生期における化学暴露が扁桃体神経興奮性に及ぼす影響の多面的評価法Multiple parameter evaluation of the altered neuronal excitability in the central amygdala of the rats with perinatal administration of ethanol, nicotine and valproate (2011)
  • Author(s): 高橋由香里、永瀬将志、落合敏平、安井豊、中尾彩乃、渡部文子、高本聡、佐藤優、奥津裕也、守口徹、佐藤薫、加藤総夫
  • Organizer: 第34回日本神経科学会大会
  • Place of Presentation: 神奈川県横浜市
• [Presentation] シナプス伝達維持におけるモノカルボン酸トランスポーター依存性エネルギーの役割Synapse type-dependent contributions of MCT-dependent energy supply to the maintenance of transmission in the rat brain (2011)
  • Author(s): Nagase, M., Watabe, A.M., Kato, F.
  • Organizer: 第34回日本神経科学会大会
  • Place of Presentation: 神奈川県横浜市
• [Presentation] 神経障害性疼痛を伴う糖尿病マウスにおける侵害受容性扁桃体のシナプス伝達増強Potentiated synaptic transmission in the nociceptive amygdala of diabetic mice with neuropathic pain (2011)
  • Author(s): Ochiai, T., Takahashi, Y., Asato, M., Watabe, A.M., Ohsawa, M., Kamei, J., Kato, F.
  • Organizer: 第34回日本神経科学会大会
  • Place of Presentation: 神奈川県横浜市
• [Presentation] Activation of the mGluR5 increases L-VDCC currents and facilitates VDCC-dependent LTP in the CA1 region of the hippocampus (2010)
  • Author(s): Kato, H., Watabe, A. M., Aiba, A., Manabe, T
  • Organizer: SFN 40th Annual meeting fo the Society for Neuroscience
  • Place of Presentation: San Diego
• [Presentation] The replacement of GluN2B with GluN2A increases synaptic trafficking of AMPA receptors in the neonatal mouse brain (2010)
  • Author(s): Hamada, S., Ogawa, I., Kiyama, Y., Watabe, A. M., Kassai, H., Nakao, K., Aiba, A., Manabe, T
  • Organizer: 第33回日本神経科学大会Neuro2010
  • Place of Presentation: 神戸
• [Presentation] Altered characteristics of vesicular release at the nociceptive amygdala of neuropathic rat (2010)
  • Author(s): Takahashi, Y., Nakao-Iwase, A., Watabe, A. M., Kato, F
  • Organizer: FENS forum
  • Place of Presentation: Amsterdam
• [Presentation] 扁桃体外側核におけるシナプス伝達のコリン作動性抑制 (2010)
  • Author(s): 田附千絵子、三輪秀樹、松井稔、渡部文子、真鍋俊也
  • Organizer: 第87回日本生理学会大会
  • Place of Presentation: 盛岡
• [Presentation] Activation of the mGluR5 increases L-VDCC currents and facilitates VDCC-dependent LTP in the CA1 region of the hippocampus (2010)
  • Author(s): Kato, H., Watabe, A.M., Aiba, A., Manabe, T.
  • Organizer: SFN 40^<th> Annual meeting of the Society for Neuroscience
  • Place of Presentation: San Diego, CA, USA
• [Presentation] Cholinergic suppression of synaptic transmission in the lateral amygdala (2009)
  • Author(s): Chieko Tazuke, Hideki Miwa, Minoru Matsui, Ayako M.Watabe, Toshiya Manabe
  • Organizer: 第32回日本神経科学会大会
  • Place of Presentation: 名古屋
• [Presentation] PROLONGED LOW-FREQUENCY STIMULATION INDUCES MITOCHONDRIA-DEPENDENT SHORT-TERM POTENTIATION ATHIPPOCAMPAL CA3-CAI SYNAPSES (2009)
  • Author(s): Morimoto, T., Watabe, A.M., Manabe, T.
  • Organizer: International congress of Physiological Sciences
  • Place of Presentation: 京都
• [Book] 「キーワードで徹底理解するシグナル伝達キーワード事典」第2部神経可塑性
  • Publisher: 羊土社