Details of the Researcher

PHOTO

Shigeki Moriguchi
Section
Graduate School of Pharmaceutical Sciences
Job title
Associate Professor
Degree

  • 博士（薬学）（九州大学）

  • 修士（薬学）（福岡大学）

Research History 8

  • 2019/11 - Present
    Research Center for Pharmaceutical Development, Graduate School of Pharmaceutical Sciences, Tohoku University　Associate Professor

  • 2010/04 - 2019/10
    Department of pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University　Senior Assistant Professor

  • 2011/04 - 2018/03
    Miyagi Gakuin Women's University　Lecturer

  • 2009/09 - 2014/08
    Department of Molecular Pharmacology and Biological Chemistry, Northwestern University, Chicago, U.S.A.　Associate Professor

  • 2007/04 - 2010/03
    Department of pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University　Assistant Professor

  • 2006/09 - 2009/08
    Department of Molecular Pharmacology and Biological Chemistry, Northwestern University, Chicago, U.S.A.　Assistant Professor

  • 2004/04 - 2007/03
    Department of pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University　Research Assistant

  • 2001/09 - 2004/03
    Department of Molecular Pharmacology and Biological Chemistry, Northwestern University, Chicago, U.S.A.　Postdoctoral Fellowship

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Education 1

  • Kyushu University　Graduate School, Division of Pharmaceutical Sciences

    - 2001/03

Professional Memberships 5

  • 日本神経精神薬理学会

  • 日本薬学会

  • 日本神経化学会

  • 日本薬理学会

  • 北米神経科学学会

Research Interests 1

  • Calcium signal, Cognitive/mental disorder, Dementia

Research Areas 1

  • Life sciences / Neuroscience - general /

Awards 13

  1. 東北大学大学院薬学研究科長賞

    2020/07

  2. 東北大学大学院薬学研究科長賞

    2019/07

  3. Tech Open 2018 優勝

    2018/08　東北大学

  4. 東北大学大学院薬学研究科長賞

    2018/07

  5. 日本神経精神薬理学会学術奨励賞

    2015/09

  6. 東北大学大学院薬学研究科長賞

    2015/07

  7. インテリジェント・コスモス奨励賞

    2015/05

  8. 東北大学大学院薬学研究科長賞

    2014/07

  9. 日本薬理学会学術奨励賞

    2011/03

  10. 日本神経化学会奨励賞

    2010/09

  11. 東北大学大学院薬学研究科長賞

    2009/07

  12. 日本薬学会東北支部奨励賞

    2008/12

  13. BP/NP/NC 2006 優秀演題賞

    2006/10

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Papers 83

  1. Aberrant extracellular dopamine clearance in the prefrontal cortex exhibit ADHD-like behavior in NCX3 heterozygous mice. Peer-reviewed

    Ryo Inagaki, Satomi Kita, Nozomu Niwa, Kohji Fukunaga, Takahiro Iwamoto, Shigeki Moriguchi

    FEBS J　292　426-444　2025

  2. Preventive effect of propolis on cognitive decline in Alzheimer’s disease model mice. Peer-reviewed

    Ryo Inagaki, Tohru Yamakuni, Takashi Saito, Takaomi C Saido, Shigeki Moriguchi

    Neurobiol Aging　139　20-29　2024

  3. Propolis promotes memantine-dependent rescue of cognitive deficits in APP-KI mice. Peer-reviewed

    Shigeki Moriguchi, Ryo Inagaki, Takashi Saito, Takaomi C. Saido, Kohji Fukunaga

    Mol Neurobiol　59　4630-4646　2022

  4. Memantine improves cognitive deficits via KATP channel inhibition in olfactory bulbectomized mice. Peer-reviewed

    Shigeki Moriguchi, Ryo Inagaki, Kohji Fukunaga

    Mol Cell Neurosci　117　103680　2021

  5. Scabronine G methyl ester improves memory-related behavior and enhances hippocampal cell proliferation and long-term potentiation via the BDNF-CREB pathway in olfactory bulbectomized mice. International-journal Peer-reviewed

    Osamu Nakagawasai, Lin Jia-Rong, Takayo Odaira, Kohei Takahashi, Wataru Nemoto, Shigeki Moriguchi, Yasushi Yabuki, Yu Kobayakawa, Kohji Fukunaga, Masahisa Nakada, Koichi Tan-No

    Front Pharmacol　11　583291-583291　2020

    DOI： 10.3389/fphar.2020.583291 　

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    A previous study reported that scabronine G methyl ester (SG-ME) potentially enhances the in vitro secretion of neurotrophic factors such as nerve growth factor via the protein kinase C (PKC)-ζ pathway. However, it remains unknown whether SG-ME can improve cognitive dysfunctions in olfactory bulbectomized (OBX) mice. To address this question, we evaluated SG-ME-treated and untreated OBX mice in a passive avoidance test. We also investigated potential effects of SG-ME on several parameters: cell proliferation and cAMP response element-binding protein (CREB) phosphorylation in the hippocampal dentate gyrus by immunohistochemistry, brain-derived neurotrophic factor (BDNF) levels in the hippocampus by Western blotting, p-CREB levels in the hippocampus by MapAnalyzer, and long-term potentiation (LTP) by electrophysiology. On the 14th day after surgery OBX mice showed altered passive avoidance and decreases in both cell proliferation and long-term potentiation in the hippocampus, while these changes were reversed by SG-ME (20 μg/mouse) 24 h after the treatment. The improvement in memory deficits was prevented when SG-ME was co-administeredwith either zeta inhibitory peptide (PKC-ζ inhibitor), anti-BDNF antibody, ANA-12 (TrkB antagonist), U0126 (MEK inhibitor), H-89 (PKA inhibitor), LY294002 (PI3K inhibitor) or KN-93 (CaMKII inhibitor). We found that SG-ME enhanced brain-derived neurotrophic factor and p-CREB levels in the hippocampus while p-CREB was localized in neurons, but not in astrocytes nor microglial cells. These findings revealed the potential of SG-ME in improving memory impairments by enhancing cell proliferation and LTP via activation of the BDNF/CREB signaling pathway in neurons.

  6. Nicotine rescues depressive-like behaviors via α7-type nicotinic acetylcholine receptor activation in CaMKIV null mice. International-journal Peer-reviewed

    Shigeki Moriguchi, Ryo Inagaki, Lusha Yi, Mikako Shibata, Hiroyuki Sakagami, Kohji Fukunaga

    Mol Neurobiol　57　4929-4940　2020

    DOI： 10.1007/s12035-020-02077-z 　

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    The nicotinic acetylcholine receptors (nAChRs) are essential for acetylcholine-mediated signaling. Two major functional subtypes of nAChR in the brain, α7-type and α4β2-type, have a high affinity for nicotine. Here, we demonstrated that chronic exposure to nicotine at 0.03-0.3 mg/kg for 14 days rescued depressive-like behavior in calcium/calmodulin-dependent protein kinase IV (CaMKIV) null mice. Chronic exposure to nicotine together with methyllycaconitine, an α7-type nAChR antagonist, but not with dihydro-β-erythroidine, an α4β2-type nAChR antagonist, failed to rescue the depressive-like behavior and restore the reduced number of BrdU-positive cells in the dentate gyrus (DG) of CaMKIV null mice. Furthermore, chronic exposure to nicotine enhanced the PI3K/Akt and ERK/CREB pathways and increased BDNF expression in the DG of CaMKIV null mice. Similar to chronic exposure to nicotine, both PNU-282987 and GTS-21, α7-type nAChR agonists, significantly rescued depressive-like behavior, with a reduction in the number of BrdU-positive cells in the DG of CaMKIV null mice. Both PNU-282987 and GTS-21 also enhanced the PI3K/Akt and ERK/CREB pathways and increased brain-derived neurotrophic factor (BDNF) expression in the DG of CaMKIV null mice. Taken together, we demonstrated that chronic exposure to nicotine rescues depressive-like behavior via α7-type nAChR through the activation of both PI3K/Akt and ERK/CREB pathways in CaMKIV null mice.

  7. Memantine improves depressive-like behaviors via Kir6.1 channel inhibition in olfactory bulbectomized mice. International-journal Peer-reviewed

    Shigeki Moriguchi, Ryo Inagaki, Hirotsugu Shimojo, Yoshihiko Sugimura, Kohji Fukunaga

    Neuroscience　442　264-273　2020

    DOI： 10.1016/j.neuroscience.2020.06.002 　

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    Aberrant depressive-like behaviors in olfactory bulbectomized (OBX) mice have been documented by previous studies. Here, we show that memantine enhances adult neurogenesis in the subgranular zone of the hippocampal dentate gyrus (DG) and improves depressive-like behaviors via inhibition of the ATP-sensitive potassium (KATP) channel in OBX mice. Treatment with memantine (1-3 mg/kg; per os (p.o.)) for 14 days significantly improved depressive-like behaviors in OBX mice, as assessed using the tail-suspension and forced-swim tests. Treatment with memantine also increased the number of BrdU-positive neurons in the DG of OBX mice. In the immunoblot analysis, memantine significantly increased phosphorylation of CaMKIV (Thr-196) and Akt (Ser-473), but not ERK (Thr-202/Tyr-204), in the DG of OBX mice. Furthermore, phosphorylation of GSK3β (Ser-9) and CREB (Ser-133), and BDNF protein expression levels increased in the DG of OBX mice, possibly accounting for the increased adult neurogenesis owing to Akt activation. In contrast, both the improvement of depressive-like behaviors and increase in BrdU-positive neurons in the DG following treatment with memantine were unapparent in OBX-treated Kir6.1 heterozygous (+/-) mice but not OBX-treated Kir6.2 heterozygous (+/-) mice. Furthermore, the increase in CaMKIV (Thr-196) and Akt (Ser-473) phosphorylation and BDNF protein expression levels was not observed in OBX-treated Kir6.1 +/- mice. Overall, our study shows that memantine improves OBX-induced depressive-like behaviors by increasing adult neurogenesis in the DG via Kir6.1 channel inhibition.

  8. Kir6.1 heterozygous mice exhibit aberrant amygdala-dependent cued fear memory International-journal Peer-reviewed

    Ryo Inagaki, Shigeki Moriguchi, Kohji Fukunaga

    Mol. Neurobiol.　57　(3)　1622-1635　2020

    DOI： 10.1007/s12035-019-01840-1 　

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    ATP-sensitive K+ (KATP) channels are predominantly expressed in the brain and consist of four identical inward-rectifier potassium ion channel subunits (Kir6.1 or Kir6.2) and four identical high-affinity sulfonylurea receptor subunits (SUR1, SUR2A, or SUR2B). We previously observed that chronic corticosterone-treated (CORT) mice exhibited enhanced anxiety-like behaviors and cued fear memory. In the present study, the protein and mRNA expression levels of Kir6.1, but not Kir6.2, were decreased in the lateral amygdala (LA) of CORT mice. Heterozygous Kir6.1-null (Kir6.1+/-) mice also showed enhanced tone (cued) fear memory and long-term potentiation (LTP) in the cortico-LA pathway compared to those in wild-type mice. However, LTP was not enhanced in the hippocampal CA1 regions of Kir6.1+/- mice. Consistent with increased cued fear memory, both Ca2+/calmodulin-dependent protein kinase II (CaMKII) and extracellular signal-regulated kinase (ERK) activities were significantly elevated in the LAs of Kir6.1+/- mice after tone stimulation. Our results indicate that increased CaMKII and ERK activities may induce LTP in the LA in Kir6.1+/- mice, leading to aberrant cued fear memory. The changes in neural plasticity in the LA of Kir6.1+/- mice were associated with anxiety-like behaviors and may be related to the pathogenic mechanisms of anxiety disorders in human patients.

  9. Aberrant amygdala-dependent cued fear memory in Na+/Ca2+ exchanger 1 heterozygous mice. Peer-reviewed

    Shigeki Moriguchi, Satomi Kita, Ryo Inagaki, Yasushi Yabuki, Yuzuru Sasaki, Shun Ishikawa, Hiroyuki Sakagami, Takahiro Iwamoto, Kohji Fukunaga

    Mol. Neurobiol.　56　4381-4394　2019

  10. Reduced CaM kinase II and CaM kinase IV activities underlie cognitive deficits in NCKX2 heterozygous mice. International-journal Peer-reviewed

    Shigeki Moriguchi, Satomi Kita, Yasushi Yabuki, Ryo Inagaki, Hisanao Izumi, Yuzuru Sasaki, Hideaki Tagashira, Kyoji Horie, Junji Takeda, Takahiro Iwamoto, Kohji Fukunaga

    Mol. Neurobiol.　55　3889-3900　2018

    DOI： 10.1007/s12035-017-0596-1 　

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    Among five members of the K+-dependent Na+/Ca2+ exchanger (NCKX) family (NCKX1-5), only NCKX2 is highly expressed in mouse brain. NCKX2 in plasma membranes mediates cytosolic calcium excretion through electrogenic exchange of 4 Na+ for 1 Ca2+ and 1 K+. Here, we observed significantly decreased levels of NCKX2 protein and mRNA in the CA1 region of APP23 mice, a model of Alzheimer's disease. We also found that, like APP23 mice, heterozygous NCKX2-mutant mice exhibit mildly impaired hippocampal LTP and memory acquisition, the latter based on novel object recognition and passive avoidance tasks. When we addressed underlying mechanisms, we found that both CaMKII autophosphorylation and CaMKIV phosphorylation significantly decreased in CA1 regions of NCKX2+/- relative to control mice. Likewise, phosphorylation of GluA1 (Ser-831) and CREB (Ser-133), respective downstream targets of CaMKII and CaMKIV, also significantly decreased in the CA1 region. BDNF protein and mRNA levels significantly decreased in CA1 of NCKX2+/- relative to control mice. Finally, CaN activity increased in CA1 of NCKX2+/- mice. Our findings suggest that like APP23 mice, NCKX2+/- mice may exhibit impaired learning and hippocampal LTP due to decreased CaM kinase II and CaM kinase IV activities.

  11. Blockade of the K ATP channel Kir6.2 by memantine represents a novel mechanism relevant to Alzheimer's disease therapy Peer-reviewed

    S. Moriguchi, T. Ishizuka, Y. Yabuki, N. Shioda, Y. Sasaki, H. Tagashira, H. Yawo, J. Z. Yeh, H. Sakagami, T. Narahashi, K. Fukunaga

    Molecular Psychiatry　23　211-221　2018

    Publisher: Nature Publishing Group

    DOI： 10.1038/mp.2016.187 　

    ISSN： 1476-5578 1359-4184

  12. Dysfunction of Na+/Ca2+ exchangers is associated with cognitive decline in Alzheimer’s disease. Peer-reviewed

    Shigeki Moriguchi, Satomi Kita, Takahiro Iwamoto, Kohji Fukunaga

    Nihon Yakurigaku Zasshi　152　(6)　299-305　2018

  13. Aberrant amygdala-dependent fear memory in corticosterone-treated mice. Peer-reviewed

    Ryo Inagaki, Shigeki Moriguchi, Kohji Fukunaga

    Neuroscience　388　448-459　2018

  14. Reduced expression of Na+/Ca2+ exchangers is associated with cognitive deficits seen in Alzheimer's disease model mice. International-journal Peer-reviewed

    Shigeki Moriguchi, Satomi Kita, Masahiro Fukaya, Makoto Osanai, Ryo Inagaki, Yuzuru Sasaki, Hisanao Izumi, Kyoji Horie, Junji Takeda, Takashi Saito, Hiroyuki Sakagami, Takaomi C Saido, Takahiro Iwamoto, Kohji Fukunaga

    Neuropharmacology　131　291-303　2018

    DOI： 10.1016/j.neuropharm.2017.12.037 　

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    Na+/Ca2+ exchangers (NCXs) are expressed primarily in the plasma membrane of most cell types, where they mediate electrogenic exchange of one Ca2+ for three Na+ ions, depending on Ca2+ and Na+ electrochemical gradients across the membrane. Three mammalian NCX isoforms (NCX1, NCX2, and NCX3) are each encoded by a distinct gene. Here, we report that NCX2 and NCX3 protein and mRNA levels are relatively reduced in hippocampal CA1 of APP23 and APP-KI mice. Likewise, NCX2+/- or NCX3+/- mice exhibited impaired hippocampal LTP and memory-related behaviors. Moreover, relative to controls, calcium/calmodulin-dependent protein kinase II (CaMKII) autophosphorylation significantly decreased in NCX2+/- mouse hippocampus but increased in hippocampus of NCX3+/- mice. NCX2 or NCX3 heterozygotes displayed impaired maintenance of hippocampal LTP, a phenotype that in NCX2+/- mice was correlated with elevated calcineurin activity and rescued by treatment with the calcineurin (CaN) inhibitor FK506. Likewise, FK506 treatment significantly restored impaired hippocampal LTP in APP-KI mice. Moreover, Ca2+ clearance after depolarization following high frequency stimulation was slightly delayed in hippocampal CA1 regions of NCX2+/- mice. Electron microscopy revealed relatively decreased synaptic density in CA1 of NCX2+/- mice, while the number of spines with perforated synapses in CA1 significantly increased in NCX3+/- mice. We conclude that memory impairment seen in NCX2+/- and NCX3+/- mice reflect dysregulated hippocampal CaMKII activity, which alters dendritic spine morphology, findings with implications for memory deficits seen in Alzheimer's disease model mice.

  15. Stimulation of the sigma-1 receptor and the effects on neurogenesis and depressive behaviors in mice Peer-reviewed

    Kohji Fukunaga, Shigeki Moriguchi

    Advances in Experimental Medicine and Biology　964　201-211　2017

    Publisher: Springer New York LLC

    DOI： 10.1007/978-3-319-50174-1_14 　

    ISSN： 2214-8019 0065-2598

  16. Combined memantine and donepezil treatment improves behavioral and psychological symptoms of dementia-like behaviors in olfactory bulbectomized mice. Peer-reviewed

    Yasushi Yabuki, Kazuya Matsuo, Koga Hirano, Yasuharu Shinoda, Shigeki Moriguchi, Kohji Fukunaga

    Pharmacology　99　(3-4)　160-171　2017

    DOI： 10.1159/000452839 　

    ISSN： 0031-7012

    eISSN： 1423-0313

  17. Memantine improves cognitive function via KATP channel inhibition. Peer-reviewed

    Shigeki Moriguchi, Kohji Fukunaga

    Nihon Yakurigaku Zasshi　150　(5)　228-233　2017

    Publisher: The Japanese Pharmacological Society

    DOI： 10.1254/fpj.150.228 　

  18. Functional genomic analyses identify pathways dysregulated in animal model of autism. Peer-reviewed

    Ji-Yun Huang, Yun Tian, Hui-Juan Wang, Hong Shen, Huan Wang, Sen Long, Mei-Hua Liao, Zhi-Rong Liu, Ze-Ming Wang, Dan Li, Rong-Rong Tao, Tian-Tian Cui, Shigeki Moriguchi, Kohji Fukunaga, Feng Han, Ying-Mei Lu

    CNS Neurosci. Ther.　22　(10)　845-853　2016

    DOI： 10.1111/cns.12582 　

    ISSN： 1755-5930

    eISSN： 1755-5949

  19. A novel therapeutic target of treatment-resistant depression. Peer-reviewed

    Shigeki Moriguchi

    Jpn. J. Neuropsychopharmacol.　36　73-78　2016

  20. Stimulation of sigma-1 receptor ameliorates depressive-like behaviors via mitochindrial ATP production in CaMKIV null mice. Peer-reviewed

    Shigeki Moriguchi, Kohji Fukunaga

    Nihon Yakurigaku Zasshi　147　(4)　206-210　2016

    Publisher: The Japanese Pharmacological Society

    DOI： 10.1254/fpj.147.206 　

    ISSN： 0015-5691

  21. The extracellular fragment of GPNMB (Glycoprotein nonmelanosoma protein B, osteoactivin) improves memory and increases hippocampal GluA1 levels in mice. Peer-reviewed

    Kenta Murata, Yuta Yoshino, Kazuhiro Tsuruma, Shigeki Moriguchi, Atsushi Oyagi, Hirotaka Tanaka, Mitsue Ishisaka, Masamitsu Shimazawa, Kohji Fukunaga, Hideaki Hara

    J. Neurochem.　132　(5)　583-594　2015

    DOI： 10.1111/jnc.13010 　

    ISSN： 0022-3042

    eISSN： 1471-4159

  22. Stimulation of sigma-1 receptor ameliorates depressive-like behaviors in CaMKIV null mice. Peer-reviewed

    Shigeki Moriguchi, Hiroyuki Sakagami, Yasushi Yabuki, Yuzuru Sasaki, Hisanao Izumi, Chen Zhang, Feng Han, Kohji Fukunaga

    Mol. Neurobiol.　52　(3)　1210-1222　2015

    DOI： 10.1007/s12035-014-8923-2 　

    ISSN： 0893-7648

    eISSN： 1559-1182

  23. Aberrant behavioral sensitization by methamphetamine in junctophilin deficient mice. Peer-reviewed

    Shigeki Moriguchi, Miyuki Nishi, Yuzuru Sasaki, Hiroshi Takeshima, Kohji Fukunaga

    Mol. Neurobiol.　51　(2)　533-542　2015

    DOI： 10.1007/s12035-014-8737-2 　

    ISSN： 0893-7648

    eISSN： 1559-1182

  24. Melatonin reverses the decreases in hippocampal protein serine/threonine kinases observed in an animal model of autism. Peer-reviewed

    Yun Tian, Yasushi Yabuki, Shigeki Moriguchi, Kohji Fukunaga, Pei-Jiang Mao, Ling-Juan Hong, Ying-Mei Lu, Rui Wang, Muhammad Masood Ahmed, Mei-Hua Liao, Ji-Yun Huang, Rui-Ting Zhang, Tian-Yi Zhou, Sen Long, Feng Han

    J. Pineal. Res.　56　(1)　1-11　2014

    DOI： 10.1111/jpi.12081 　

    ISSN： 0742-3098

    eISSN： 1600-079X

  25. CaMKII activity is essential for improvement of memory-related behaviors by chronic rivastigmine treatment. Peer-reviewed

    Shigeki Moriguchi, Hideaki Tagashira, Yuzuru Sasaki, Jay Z. Yeh, Hiroyuki Sakagami, Toshio Narahashi, Kohji Fukunaga

    J. Neurochem.　128　(6)　927-937　2014

    DOI： 10.1111/jnc.12510 　

    ISSN： 0022-3042

    eISSN： 1471-4159

  26. Rivastigmine improves hippocampal neurogenesis and depressive-like behaviors via 5-HT1A receptor stimulation in olfactory bulbectomized mice. Peer-reviewed

    Muhammad Rashedul Islam, Shigeki Moriguchi, Hideaki Tagashira, Kohji Fukunaga

    Neuroscience　272　116-130　2014

    DOI： 10.1016/j.neuroscience.2014.04.046 　

    ISSN： 0306-4522

    eISSN： 1873-7544

  27. Rivastigmine restores 5-HT1A receptor levels in the hippocampus of olfactory bulbectomized mice. Peer-reviewed

    Muhammad Rashedul Islam, Shigeki Moriguchi, Hideaki Tagashira, Kohji Fukunaga

    Adv. Alzheimer’s Dis.　3　128-136　2014

  28. Decreased CaMKII and PKC activities in specific brain regions are associated with cognitive impairment in neonatal ventral hippocampus-lesioned rats. International-journal Peer-reviewed

    Y Yabuki, O Nakagawasai, S Moriguchi, N Shioda, H Onogi, K Tan-No, T Tadano, K Fukunaga

    Neuroscience　234　103-15　2013

    DOI： 10.1016/j.neuroscience.2012.12.048 　

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    Neonatal ventral hippocampus (NVH)-lesioned rats represent a neurodevelopmental impairment model of schizophrenia. Previous observations indicate that postpubertal NVH-lesioned rats exhibit impairments in prepulse inhibition (PPI), spontaneous locomotion and social interaction behavior. Here, we document the neurochemical basis of those defects. PPI impairment but not cognitive impairment was improved by acute risperidone treatment (0.30mg/kgi.p.). Immunohistochemical analyses using anti-autophosphorylated Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) antibody indicated significantly reduced CaMKII autophosphorylation, especially in the medial prefrontal cortex (mPFC), striatum and hippocampal CA1 region, of NVH-lesioned rats relative to control animals. We also confirmed that reduced CaMKII autophoshorylation in the mPFC, striatum and hippocampal CA1 region causes decreased phosphorylation of α-amino-3-hydroxy-5-methyl-4-isoxazolpropionic acid-type glutamate receptor subunit 1 (GluR1) (Ser 831), a CaMKII substrate. Like CaMKII, PKCα (Ser 657) autophosphorylation and NR1 (Ser 896) phosphorylation were decreased both in the mPFC and CA1 region. Interestingly, phosphorylation of DARPP-32 (Thr 34) was decreased in the mPFC but increased in the striatum and CA1 region of NVH-lesioned rats compared to controls. Risperidone treatment restored increased DARPP-32 phosphorylation in the striatum and CA1 regions of NVH-lesioned rats but did not rescue CaMKII and PKCα autophosphorylation. Taken together, we find that impaired cognition observed in NVH-lesioned rats is associated with decreased CaMKII and PKCα activities in memory-related brain regions, changes not rescued by risperidone treatment.

  29. Novel nootropic drug sunifiram improves cognitive deficits via CaM kinase II and protein kinase C activation in olfactory bulbectomized mice Peer-reviewed

    Shigeki Moriguchi, Tomoya Tanaka, Hideaki Tagashira, Toshio Narahashi, Kohji Fukunaga

    Behav. Brain. Res.　242　150-157　2013

    DOI： 10.1016/j.bbr.2012.12.054 　

    ISSN： 0166-4328

    eISSN： 1872-7549

  30. The novel cognitive enhancer, ST101, enhances acetylcholine release in mouse dorsal hippocampus through T-type voltage-gated calcium channel stimulation. Peer-reviewed

    Yui Yamamoto, Norifumi Shioda, Feng Han, Shigeki Moriguchi, Kohji Fukunaga

    J. Pharmacol. Sci.　121　(3)　212-226　2013

    DOI： 10.1254/jphs.12233FP 　

    ISSN： 1347-8613

  31. Stimulation of the sigma-1 receptor by DHEA enhances synaptic efficacy and neurogenesis in the hippocampal dentate gyrus of olfactory bulbectomized mice. Peer-reviewed

    Shigeki Moriguchi, Yasuharu Shinoda, Yui Yamamoto, Yuzuru Sasaki, Kosuke Miyajima, Hideaki Tagashira, Kohji Fukunaga

    PLoS One　8　(4)　e60863　2013

    DOI： 10.1371/journal.pone.0060863 　

    ISSN： 1932-6203

  32. Novel nootropic drug sunifiram enhances hippocampal synaptic efficacy via glycine binding site of N-methyl-D-aspartate receptor. Peer-reviewed

    Shigeki Moriguchi, Tomoya Tanaka, Toshio Narahashi, Kohji Fukunaga

    Hippocampus　23　(10)　942-951　2013

    DOI： 10.1002/hipo.22150 　

    ISSN： 1050-9631

  33. Aberrant hippocampal spine morphology and impaired memory formation in neuronal platelet-derived growth factor β-receptor lacking mice. International-journal Peer-reviewed

    Norifumi Shioda, Shigeki Moriguchi, Takeshi Oya, Yoko Ishii, Jie Shen, Takako Matsushima, Hisao Nishijo, Masakiyo Sasahara, Kohji Fukunaga

    Hippocampus　22　(6)　1371-8　2012

    DOI： 10.1002/hipo.20973 　

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    The physiological role of platelet-derived growth factor (PDGF) in the central nervous system (CNS) synaptic function remains uncharacterized. Here we identify physiological roles of PDGF receptor-β (PDGFR-β) in the CNS by conditional knockout of the gene encoding it. In the hippocampus, PDGFR-β colocalized immunohistochemically with both presynaptic synaptophysin and postsynaptic density-95 (PSD-95). In the hippocampal CA1 region, expression levels of postsynaptic proteins, including spinophilin, drebrin, and PSD-95, were significantly decreased in PDGFR-β knockout mice, although presynaptic synaptophysin levels remained comparable to controls. Interestingly, in hippocampal CA1 pyramidal neurons, dendritic spine density in PDGFR-β knockout mice was significantly decreased compared with that seen in wild-type mice, although spine length and number of dendritic branches remained unchanged. Consistent with these findings, impairment in hippocampal long-term potentiation (LTP) and in hippocampus-dependent memory formation were seen in PDGFR-β knockout mice. These results suggest PDGFR-β plays critical roles in spine morphology and memory formation in mouse brain.

  34. Reduced calcium/calmodulin-dependent protein kinase II activity in the hippocampus is associated with impaired cognitive function in MPTP-treated mice. Peer-reviewed

    Shigeki Moriguchi, Yasushi Yabuki, Kohji Fukunaga

    J. Neurochem.　120　(4)　541-551　2012

    DOI： 10.1111/j.1471-4159.2011.07608.x 　

    ISSN： 0022-3042

  35. The T-type voltage-gated calcium channel as a molecular target of the novel cognitive enhancer ST101: enhancement of long-term potentiation and CaMKII autophosphorylation in rat cortical slices. Peer-reviewed

    Shigeki Moriguchi, Norifumi Shioda, Yui Yamamoto, Hideaki Tagashira, Kohji Fukunaga

    J. Neurochem.　121　(1)　44-53　2012

    DOI： 10.1111/j.1471-4159.2012.07667.x 　

    ISSN： 0022-3042

  36. Ca2+/calmodulin-dependent protein kinase II and protein kinase C activities mediate extracellular glucose-regulated hippocampal synaptic efficacy. Peer-reviewed

    Shigeki Moriguchi, Yutaka Oomura, Norifumi Shioda, Feng Han, Nobuaki Hori, Shuji Aou, Kohji Fukunaga

    Mol. Cell. Neurosci.　46　(1)　101-107　2011

    DOI： 10.1016/j.mcn.2010.08.010 　

    ISSN： 1044-7431

  37. Reduced expression of the ATRX gene, a chromatin-remodeling factor, causes hippocampal dysfunction in mice. International-journal Peer-reviewed

    Tatsuya Nogami, Hideyuki Beppu, Takashi Tokoro, Shigeki Moriguchi, Norifumi Shioda, Kohji Fukunaga, Toshihisa Ohtsuka, Yoko Ishii, Masakiyo Sasahara, Yutaka Shimada, Hisao Nishijo, En Li, Isao Kitajima

    Hippocampus　21　(6)　678-87　2011

    DOI： 10.1002/hipo.20782 　

    More details Close

    Mutations of the ATRX gene, which encodes an ATP-dependent chromatin-remodeling factor, were identified in patients with α-thalassemia X-linked mental retardation (ATR-X) syndrome. There is a milder variant of ATR-X syndrome caused by mutations in the Exon 2 of the gene. To examine the impact of the Exon 2 mutation on neuronal development, we generated ATRX mutant (ATRX(ΔE2)) mice. Truncated ATRX protein was produced from the ATRX(ΔE2) mutant allele with reduced expression level. The ATRX(ΔE2) mice survived and reproduced normally. There was no significant difference in Morris water maze test between wild-type and ATRX(ΔE2) mice. In a contextual fear conditioning test, however, total freezing time was decreased in ATRX(ΔE2) mice compared to wild-type mice, suggesting that ATRX(ΔE2) mice have impaired contextual fear memory. ATRX(ΔE2) mice showed significantly reduced long-term potentiation in the hippocampal CA1 region evoked by high-frequency stimulation. Moreover, autophosphorylation of calcium-calmodulin-dependent kinase II (αCaMKII) and phosphorylation of glutamate receptor, ionotropic, AMPA 1 (GluR1) were decreased in the hippocampi of the ATRX(ΔE2) mice compared to wild-type mice. These findings suggest that ATRX(ΔE2) mice may have fear-associated learning impairment with the dysfunction of αCaMKII and GluR1. The ATRX(ΔE2) mice would be useful tools to investigate the role of the chromatin-remodeling factor in the pathogenesis of abnormal behaviors and learning impairment.

  38. Sigma-1 receptor stimulation by dehydroepiandrosterone ameliorates cognitive impairment through activation of CaM kinase II, protein kinase C and extracellular signal-regulated kinase in olfactory bulbectomized mice. Peer-reviewed

    Shigeki Moriguchi, Yui Yamamoto, Tatsuya Ikuno, Kohji Fukunaga

    J. Neurochem.　117　(5)　879-891　2011

    DOI： 10.1111/j.1471-4159.2011.07256.x 　

    ISSN： 0022-3042

    eISSN： 1471-4159

  39. Pharmacological study on Alzheimer's drugs targeting for calcium/calmodulin-dependent protein kinase II. Peer-reviewed

    Shigeki Moriguchi

    J. Pharmacol. Sci.　117　(1)　6-11　2011

    DOI： 10.1254/jphs.11R06CP 　

    ISSN： 1347-8613

    eISSN： 1347-8648

  40. Heparin-binding EGF-like growth factor is required for synaptic plasticity and memory formation. Peer-reviewed

    Atsushi Oyagi, Shigeki Moriguchi, Atsumi Nitta, Kenta Murata, Yasuhisa Oida, Kazuhiro Tsuruma, Masamitsu Shimazawa, Kohji Fukunaga, Hideaki Hara

    Brain Res.　1419　97-104　2011

    DOI： 10.1016/j.brainres.2011.09.003 　

    ISSN： 0006-8993

  41. Neurochemical mechanisms of a novel Alzheimer’s disease therapeutics on improvement of cognition and depressive behavior. Peer-reviewed

    Norifumi Shioda, Yui Yamamoto, Feng Han, Shigeki Moriguchi, Kohji Fukunaga

    Yakugaku Zasshi　131　(4)　505-511　2011

    DOI： 10.1248/yakushi.131.505 　

    ISSN： 0031-6903

  42. The induction of reactive oxygen species and loss of mitochondrial Omi/HtrA2 is associated with S-nitrosoglutathione-induced apoptosis in human endothelial cells Peer-reviewed

    Qi-bing Liu, Lu-lu Liu, Ying-mei Lu, Rong-rong Tao, Ji-yun Huang, Norifumi Shioda, Shigeki Moriguchi, Kohji Fukunaga, Feng Han, Yi-jia Lou

    Toxicology and Applied Pharmacology　244　(3)　374-384　2010

    DOI： 10.1016/j.taap.2010.02.004 　

    ISSN： 0041-008X 1096-0333

  43. A novel cognitive enhancer, ZSET1446/ST101, promotes hippocampal neurogenesis and ameliorates depressive behavior in olfactory bulbectomized mice Peer-reviewed

    Norifumi Shioda, Yui Yamamoto, Feng Han, Shigeki Moriguchi, Yoshimasa Yamaguchi, Masataka Hino, Kohji Fukunaga

    Journal of Pharmacology and Experimental Therapeutics　333　(1)　43-50　2010

    DOI： 10.1124/jpet.109.163535 　

    ISSN： 0022-3565 1521-0103

  44. Platelet-activating factor-induced synaptic facilitation is associated with increased calcium/calmodulin-dependent protein kinase II, protein kinase C and extracellular signal-regulated kinase activities in the rat hippocampal CA1 region. Peer-reviewed

    Shigeki Moriguchi, Norifumi Shioda, Yui Yamamoto, Kohji Fukunaga

    Neuroscience　166　(4)　1158-1166　2010

    DOI： 10.1016/j.neuroscience.2010.01.008 　

    ISSN： 0306-4522

    eISSN： 1873-7544

  45. Essential role of meuron-enriched diacylglycerol kinase (DGK), DGKβ in neurite spine formation, contributing to cognitive function. Peer-reviewed

    Yasuhito Shirai, Takeshi Kouzuki, Kenichi Kakefuda, Shigeki Moriguchi, Atsushi Oyagi, Kyoji Horie, Shin-ya Morita, Masamitsu Shimazawa, Kohji Fukunaga, Junji Takeda, Naoaki Saito, Hideaki Hara

    PLoS One　5　(7)　e11602　2010

    DOI： 10.1371/journal.pone.0011602 　

    ISSN： 1932-6203

  46. Donepezil-induced neuroprotection of acetylcholinergic neurons in olfactory bulbectomized mice. Peer-reviewed

    Yui Yamamoto, Norifumi Shioda, Feng Han, Shigeki Moriguchi, Kohji Fukunaga

    Yakugaku Zasshi　130　(5)　717-721　2010

    DOI： 10.1248/yakushi.130.717 　

    ISSN： 0031-6903

  47. Generation and Characterization of Conditional Heparin-Binding EGF-Like Growth Factor Knockout Mice. Peer-reviewed

    Atsushi Oyagi, Yasuhisa Oida, Kenichi Kakefuda, Masamitsu Shimazawa, Norifumi Shioda, Shigeki Moriguchi, Kiyoyuki Kitaichi, Daisuke Nanba, Kazumasa Yamaguchi, Yasuhide Furuta, Kohji Fukunaga, Shigeki Higashiyama, Hideaki Hara

    PLoS One　4　(10)　e7461　2009

    DOI： 10.1371/journal.pone.0007461 　

    ISSN： 1932-6203

  48. Nobiletin improves brain ischemia-induced learning and memory deficits through stimulation of CaMKII and CREB phosphorylation. Peer-reviewed

    Yui Yamamoto, Norifumi Shioda, Feng Han, Shigeki Moriguchi, Akira Nakajima, Akihito Yokosuka, Yoshihiro Mimaki, Yutaka Sashida, Tohru Yamakuni, Yasushi Ohizumi, Kohji Fukunaga

    Brain Res.　1295　218-229　2009

    DOI： 10.1016/j.brainres.2009.07.081 　

    ISSN： 0006-8993

    eISSN： 1872-6240

  49. Nefiracetam activation of CaM kinase II and protein kinase C mediated by NMDA and metabotropic glutamate receptors in olfactory bulbectomized mice. Peer-reviewed

    Shigeki Moriguchi, Feng Han, Norifumi Shioda, Yui Yamamoto, Takeharu Nakajima, Osamu Nakagawasai, Takeshi Tadano, Jay Z. Yeh, Toshio Narahashi, Kohji Fukunaga

    J. Neurochem.　110　(1)　170-181　2009

    DOI： 10.1111/j.1471-4159.2009.06122.x 　

    ISSN： 0022-3042

  50. Nefiracetam and galantamine modulation of excitatory and inhibitory synaptic transmission via stimulation of neuronal nicotinic acetylcholine receptors in rat cortical neurons. Peer-reviewed

    Shigeki Moriguchi, Xilong Zhao, William Marszalec, Jay Z Yeh, Kohji Fukunaga, Toshio Narahashi

    Neuroscience　160　(2)　484-491　2009

    DOI： 10.1016/j.neuroscience.2009.02.055 　

    ISSN： 0306-4522

  51. Galantamine enhancement of long-term potentiation is mediated by calcium/calmodulin-dependent protein kinase II and protein kinase C activation. Peer-reviewed

    Shigeki Moriguchi, Norifumi Shioda, Feng Han, Jay Z. Yeh, Toshio Narahashi, Kohji Fukunaga

    Hippocampus　19　(9)　844-854　2009

    DOI： 10.1002/hipo.20572 　

    ISSN： 1050-9631

  52. Phenylephrine-induced cardiomyocyte injury is triggered by superoxide generation through uncoupled endothelial nitric-oxide synthase and ameliorated by 3-[2-[4-(3-chloro-2-methylphenyl)-1-piperazinyl] ethyl]-5,6-dimethoxyindazole (DY-9836), a novel calmodulin antagonist. Peer-reviewed

    Ying-Mei Lu, Feng Han, Norifumi Shioda, Shigeki Moriguchi, Yasufumi Shirasaki, Zheng-Hong Qin, Kohji Fukunaga

    Mol. Pharmacol.　75　(1)　101-112　2009

    DOI： 10.1124/mol.108.050716 　

    ISSN： 0026-895X

  53. Prandial increases of leptin and orexin in the brain modulate spatial learning and memory. Peer-reviewed

    Yutaka Oomura, Shuji Aou, Kohji Fukunaga, Shigeki Moriguchi, Kazuo Sasaki

    Ross. Fiziol. Zh. Im. I .M. Sechenova　95　1373-1385　2009

  54. CaM kinase II and protein kinase C activations mediate enhancement of long-term potentiation by nefiracetam in the rat hippocampal CA1 region. Peer-reviewed

    Shigeki Moriguchi, Norifumi Shioda, Feng Han, Toshio Narahashi, Kohji Fukunaga

    J. Neurochem.　106　(3)　1092-1103　2008

    DOI： 10.1111/j.1471-4159.2008.05440.x 　

    ISSN： 0022-3042

    eISSN： 1471-4159

  55. Functional crosstalk between cell-surface and intracellular channels mediated by junctophilins essential for neuronal functions. Peer-reviewed

    Sho Kakizawa, Shigeki Moriguchi, Atsushi Ikeda, Masamitsu Iino, Hiroshi Takeshima

    Cerebellum　7　(3)　385-391　2008

    DOI： 10.1007/s12311-008-0040-1 　

    ISSN： 1473-4222

  56. Cardioprotective effect of vanadyl sulfate on ischemia/reperfusion-induced injury in rat heart in vivo is mediated by activation of protein kinase B and induction of FLICE-inhibitory protein. Peer-reviewed

    Md. Shenuarin Bhuiyan, Yoko Takada, Norifumi Shioda, Shigeki Moriguchi, Jiro Kasahara, Kohji Fukunaga

    Cardiovasc. Ther.　26　(1)　10-23　2008

    DOI： 10.1111/j.1527-3466.2008.00039.x 　

    ISSN： 1755-5914

  57. Spino[imidazo[1,2-a]pyridine-3,2-indan]-2(3H)-one (ZSET1446/ST101) treatment rescues olfactory bulbectomy-induced memory impairment by activating Ca2+/Calmodulin kinase II and protein kinase C in mouse hippocampus. Peer-reviewed

    Feng Han, Norifumi Shioda, Shigeki Moriguchi, Yui Yamamoto, Alisa Y. Ali Raie, Yoshimasa Yamaguchi, Masataka Hino, Kohji Fukunaga

    J. Pharmacol. Exp. Ther.　326　(1)　127-134　2008

    DOI： 10.1124/jpet.108.137471 　

    ISSN： 0022-3565

    eISSN： 1521-0103

  58. Nobiletin, a citrus flavonoid with neurotrophic action, augments protein kinase A-mediated phosphorylation of the AMPA receptor subunit, GluR1, and the postsynaptic receptor response to glutamate in murine hippocampus. Peer-reviewed

    Kentaro Matsuzaki, Kenichi Miyazaki, Seiichiro Sakai, Hiromu Yawo, Norihito Nakata, Shigeki Moriguchi, Kohji Fukunaga, Akihito Yokosuka, Yutaka Sashida, Yoshihiro Mimaki, Tohru Yamakuni, Yasushi Ohizumi

    Eur. J. Pharmacol.　578　(2-3)　194-200　2008

    DOI： 10.1016/j.ejphar.2007.09.028 　

    ISSN： 0014-2999

    eISSN： 1879-0712

  59. Downregulation of glutamate transporters is associated with elevation in extracellular glutamate concentration following rat microsphere embolism. Peer-reviewed

    Feng Han, Norifumi Shioda, Shigeki Moriguchi, Zheng-Hong Qin, Kohji Fukunaga

    Neurosci. Lett.　430　(3)　275-280　2008

    DOI： 10.1016/j.neulet.2007.11.021 　

    ISSN： 0304-3940

  60. The vanadium (IV) compound rescues septo-hippocampal cholinergic neurons from neurodegeneration in olfactory bulbectomized mice. Peer-reviewed

    Feng Han, Norifumi Shioda, Shigeki Moriguchi, Zheng-Hong Qin, Kohji Fukunaga

    Neuroscience　151　(3)　671-679　2008

    DOI： 10.1016/j.neuroscience.2007.11.011 　

    ISSN： 0306-4522

    eISSN： 1873-7544

  61. Nefiracetam potentiates N-methyl-D-aspartate (NMDA) receptor function via protein kinase C activation and reduces magnesium block of NMDA receptor. Invited Peer-reviewed

    Shigeki Moriguchi, Norifumi Shioda, Hiroshi Maejima, Xilong Zhao, William Marszalec, Jay Z. Yeh, Kohji Fukunaga, Toshio Narahashi

    Mol. Pharmacol.　71　(2)　580-587　2007

    DOI： 10.1124/mol.106.027607 　

    ISSN： 0026-895X

  62. Effects of ethanol on excitatory and inhibitory synaptic transmission in rat cortical neurons. Invited Peer-reviewed

    Shigeki Moriguchi, Xilong Zhao, William Marszalec, Jay Z. Yeh, Toshio Narahashi

    Alcoholism: Clin. Exp. Res.　31　(1)　89-99　2007

    DOI： 10.1111/j.1530-0277.2006.00266.x 　

    ISSN： 0145-6008

  63. Constitutively active calcineurin mediates delayed neuronal death through Fas-ligand expression via activation of NFAT and FKHR transcriptional activities in mouse brain ischemia. Invited Peer-reviewed

    Norifumi Shioda, Feng Han, Shigeki Moriguchi, Kohji Fukunaga

    J. Neurochem.　102　(5)　1506-1517　2007

    DOI： 10.1111/j.1471-4159.2007.04600.x 　

    ISSN： 0022-3042

  64. Activation of phosphatidylinositol 3-kinase/protein kinase B pathway by a vanadyl compound mediates its neuroprotective effect in mouse brain ischemia. Invited Peer-reviewed

    Norifumi Shioda, Takao Ishigami, Feng Han, Shigeki Moriguchi, Masatoshi Shibuya, Yoshiharu Iwabuchi, Kohji Fukunaga

    Neuroscience　148　(1)　221-229　2007

    DOI： 10.1016/j.neuroscience.2007.05.040 　

    ISSN： 0306-4522

  65. Cytoprotective effect of bis(1-oxy-2-pyridinethiolato)oxovanadiun(IV) on myocardial ischemia/reperfusion injury elicits inhibition of Fas ligand and Bim expression and elevation of FLIP expression. Peer-reviewed

    Md. Shenuarin Bhuiyan, Masatoshi Shibuya, Norifumi Shioda, Shigeki Moriguchi, Jiro Kasahara, Yosiharu Iwabuchi, Kohji Fukunaga

    Eur. J. Pharmacol.　571　(2-3)　180-188　2007

    DOI： 10.1016/j.ejphar.2007.05.046 　

    ISSN： 0014-2999

  66. Imbalance between CaM kinase II and calcineurin activities impairs caffeine-induced calcium release in hypertrophic cardiomyocytes. Peer-reviewed

    Ying-Mei Lu, Norifumi Shioda, Feng Han, Shigeki Moriguchi, Jiro Kasahara, Yasufumi Shirasaki, Zheng-Hong Qin, Kohji Fukunaga

    Biochem. Pharmacol.　74　(12)　1727-1737　2007

    DOI： 10.1016/j.bcp.2007.08.022 　

    ISSN： 0006-2952

  67. Decreased calcium/calmodulin-dependent protein kinase II and protein kinase C activities mediate impairment of hippocampal long-term potentiation in the olfactory bulbectomized mice. Peer-reviewed

    Shigeki Moriguchi, Feng Han, Osamu Nakagawasai, Takeshi Tadano, Kohji Fukunaga

    J. Neurochem.　97　(1)　22-29　2006

    DOI： 10.1111/j.1471-4159.2006.03710.x 　

    ISSN： 0022-3042

  68. Generation of constitutively active calcineurin by calpain contributes to delayed neuronal death following mouse brain ischemia. Peer-reviewed

    Norifumi Shioda, Shigeki Moriguchi, Yasufumi Shirasaki, Kohji Fukunaga

    J. Neurochem.　98　(1)　310-320　2006

    DOI： 10.1111/j.1471-4159.2006.03874.x 　

    ISSN： 0022-3042

  69. Lithium-induced activation of Akt and CaM kinase II contribute to its neuroprotective action in rat microsphere embolism model. Peer-reviewed

    Takuya Sasaki, Feng Han, Norifumi Shioda, Shigeki Moriguchi, Jiro Kasahara, Koichi Ishiguro, Kohji Fukunaga

    Brain Res.　1108　98-106　2006

    DOI： 10.1016/j.brainres.2006.06.009 　

    ISSN： 0006-8993

  70. DY-9760e, a novel calmodulin inhibitor, exhibits cardioprotective effects in the ischemic heart Invited Peer-reviewed

    Kohji Fukunaga, Feng Han, Norifumi Shioda, Shigeki Moriguchi, Jiro Kasahara, Yasufumi Shirasaki

    Cardiovascular Drug Reviews　24　(2)　88-100　2006

    DOI： 10.1111/j.1527-3466.2006.00088.x 　

    ISSN： 0897-5957

  71. Functional uncoupling between Ca2+ release and afterhyperpolarization in mutant hippocampal neurons lacking junctophilins. Peer-reviewed

    Shigeki Moriguchi, Miyuki Nishi, Shinji Komazaki, Hiroyuki Sakagami, Taisuke Miyazaki, Haruko Masumiya, Shin-ya Saito, Masahiko Watanabe, Hisatake Kondo, Hiromu Yawo, Kohji Fukunaga, Hiroshi Takeshima

    Proc. Natl. Acad. Sci. USA　103　(28)　10811-10816　2006

    DOI： 10.1073/pnas.0509863103 　

    ISSN： 0027-8424

  72. Modulation of N-methyl-D-aspartate receptors by donepezil in rat cortical neurons. Peer-reviewed

    Shigeki Moriguchi, Xilong Zhao, William Marszalec, Jay Z Yeh, Toshio Narahashi

    J. Pharmacol. Exp. Ther.　315　(1)　125-135　2005

    DOI： 10.1124/jpet.105.087908 　

    ISSN： 0022-3565

  73. Inhibition of nitric oxide production and protein tyrosine nitration contribute to neuroprotection by a novel calmodulin antagonist, DY-9760e, in the rat microsphere embolism. Peer-reviewed

    Takashi Shirakura, Feng Han, Norifumi Shioda, Shigeki Moriguchi, Jiro Kasahara, Toshiyuki Sato, Yasufumi Shirasaki, Kohji Fukunaga

    Biol. Pharm. Bull.　28　(9)　1658-1661　2005

    DOI： 10.1248/bpb.28.1658 　

    ISSN： 0918-6158

  74. Anesthetics modulate the release of glutamate and GABA via neuronal nicotinic acetylcholine receptors. Peer-reviewed

    Shigeki Moriguchi, William Marszalec, Xilong Zhao, Jay Z Yeh, Toshio Narahashi

    Basic and Systemic Mechanisms of Anesthesia　1283　43-48　2005

    DOI： 10.1016/j.ics.2005.07.051 　

  75. Mechanism of action of galantamine on N-Methyl-D-Aspartate receptors in rat cortical neurons. Peer-reviewed

    Shigeki Moriguchi, William Marszalec, Xilong Zhao, Jay Z Yeh, Toshio Narahashi

    J. Pharmacol. Exp. Ther.　310　(3)　933-942　2004

    DOI： 10.1124/jpet.104.067603 　

    ISSN： 0022-3565

  76. Mechanism of action of cognitive enhancer on neuroreceptors. Peer-reviewed

    Toshio Narahashi, Shigeki Moriguchi, Xilong Zhao, William Marszalec, Jay Z Yeh

    Biol. Pharm. Bull.　27　(11)　1701-1706　2004

    DOI： 10.1248/bpb.27.1701 　

    ISSN： 0918-6158

  77. Potentiation of NMDA receptor-mediated synaptic responses by microglia. Peer-reviewed

    Shigeki Moriguchi, Yoshito Mizoguchi, Yoshiro Tomimatsu, Yoshinori Hayashi, Tomoko Kadowaki, Yoshifumi Kagamiishi, Nobuo Katsube, Kenji Yamamoto, Kazuhide Inoue, Shigenori Watanabe, Junichi Nabekura, Hiroshi Nakanishi

    Mol. Brain Res.　119　(2)　160-169　2003

    DOI： 10.1016/j.molbrainres.2003.09.007 　

    ISSN： 0169-328X

  78. Potentiation of N-methyl-D-aspartate-induced currents by the nootropic drug nefiracetam in rat cortical neurons. Peer-reviewed

    Shigeki Moriguchi, William Marszalec, Xilong Zhao, Jay Z Yeh, Toshio Narahashi

    J. Pharmacol. Exp. Ther.　307　(1)　160-167　2003

    DOI： 10.1124/jpet.103.050823 　

    ISSN： 0022-3565

  79. Unique mechanism of action of Alzheimer's drugs on brain nicotinic acetylcholine receptors and NMDA receptors. Peer-reviewed

    Toshio Narahashi, William Marszalec, Shigeki Moriguchi, Jay Z Yeh, Xilong Zhao

    Life Sci.　74　(2-3)　281-291　2003

    DOI： 10.1016/j.lfs.2003.09.015 　

    ISSN： 0024-3205

    eISSN： 1879-0631

  80. Enhancement of N-methyl-D-aspartate receptor-mediated excitatory postsynaptic potentials in the neostriatum after methamphetamine sensitization: An in vitro slice study. Invited Peer-reviewed

    Shigeki Moriguchi, Shigenori Watanabe, Hitoshi Kita, Hiroshi Nakanishi

    Exp. Brain Res.　144　(2)　238-246　2002

    DOI： 10.1007/s00221-002-1039-3 　

    ISSN： 0014-4819

  81. Proteases involved in long-term potentiation. Peer-reviewed

    Yoshiro Tomimatsu, Satoru Idemoto, Shigeki Moriguchi, Shigenori Watanabe, Hiroshi Nakanishi

    Life Sci.　72　(4-5)　355-361　2002

    DOI： 10.1016/S0024-3205(02)02285-3 　

    ISSN： 0024-3205

  82. Involvement of enhanced sensitivity of N-methyl-D-aspartate receptors in vulnerability of developing cortical neurons to methylmercury neurotoxicity Peer-reviewed

    Ken-ichiro Miyamoto, Hiroshi Nakanishi, Shigeki Moriguchi, Naoto Fukuyama, Komyo Eto, Junji Wakamiya, Koji Murao, Kimiyoshi Arimura, Mitsuhiro Osame

    Brain Research　901　(1-2)　252-258　2001

    DOI： 10.1016/S0006-8993(01)02281-8 　

    ISSN： 0006-8993

  83. Central adoministration of a nitric oxide synthase inhibitor causes pressor responses via the sympathetic nervous system and the renin-angiotensin system in wistar rats. Peer-reviewed

    Shigeki Moriguchi, Noriyasu Ohzuru, Nobuhiro Koga, Kenji Honda, Ryo Saito, Yukio Takano, Hiro-o Kamiya

    Neurosci. Lett.　245　(2)　109-112　1998

    DOI： 10.1016/S0304-3940(98)00182-7 　

    ISSN： 0304-3940

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Research Projects 16

  1. カルシウム恒常性破綻による認知・精神機能障害の病態機序解明 Competitive

    2004/04 - Present

  2. カルシウムシグナル賦活化によるアルツハイマー病創薬研究 Competitive

    2001/09 - Present

  3. KATPチャネルを標的としたアルツハイマー病周辺症状の病態発症機序の解明

    森口 茂樹

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 基盤研究(C)

    Institution: 東北大学

    2021/04/01 - 2024/03/31

    More details Close

    本プロジェクトでは、アルツハイマー病（AD）周辺症状を標的とした新規MOA（mode of action）による治療法確立に向けたAD病態発症機序の解明を目指す。申請者は、AD既存薬であるmemantineの新規作用機序としてATP感受性カリウム（KATP）チャネル抑制作用（Kir6.2チャネル抑制作用：認知機能改善効果、Kir6.1チャネル抑制作用：うつ症状改善効果を報告した。本プロジェクトでは、KATPチャネルに着目したAD周辺症状の病態発症機序の解明を目指し、AD新規治療戦略の構築を目指す。2021年度は、APP-KIマウスならびにKir6.2チャネル欠損マウスを用いて、BPSDの主症状である行動障害（攻撃性症状）について検証した。検証の結果については下記の通りである。1)APP-KIマウスにおいて、対照群（野生型）と比較すると、攻撃性症状の亢進が確認された。（Resident-intruder taskによる行動解析により評価）2) APP-KIマウスの大脳皮質において、Kir6.2チャネルの発現量の低下を確認した。（免疫ブロット法による評価）3)Kir6.2チャネル欠損マウスにおいて、対照群（野生型）と比較すると、攻撃性症状の亢進が確認された。（Resident-intruder taskによる行動解析により評価）4) Kir6.2チャネル欠損マウスの大脳皮質では、セロトニン神経系の機能低下が惹起されていることを確認した。（免疫ブロット法による評価）以上の結果より、APP-KIマウスならびにKir6.2チャネル欠損マウスにおいて行動障害（攻撃性症状の亢進）が惹起していることを同定できており、次年度には、より詳細な解析（マイクロダイアリシス法、電気生理学法等）を実施する。

  4. Mechanisms of both cognitive deficits and behavioral and psychological symptoms of Alzheimer's disease in KATP channel mutant mice

    Moriguchi Shigeki

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (C)

    Institution: Tohoku University

    2018/04/01 - 2021/03/31

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    Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by both cognitive deficits and behavioral and psychological symptoms of dementia (BPSD). Here, we demonstrated that mutant mice in Kir6.2 channel observed both cognitive deficits and aggressive behaviors. By contrast, mutant mice in Kir6.1 channel observed anxiety-like behaviors, depressive-like behaviors and aggressive behaviors. In this study, we performed that detection of brain region at behavioral phenotypes and mechanisms of intracellular signaling, therefore, we detected psychological role of KATP channel in both cognitive deficits and BPSD of AD.

  5. Drug development of novel Kir6.2 channel inhibitor target for Alzheimer'ddisease

    Moriguchi Shigeki, Fukunaga Kohji

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (C)

    Institution: Tohoku University

    2015/04/01 - 2018/03/31

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    We recently discovered a novel mechanism of memory improvement by memantine via inhibition of ATP-sensitive K+ (KATP) channels. Inhibition of Kir6.2 channel by memantine improved brain insulin signaling. These results relate to brain diabetes theory causative for Alzheimer’s disease. Therefore, we have searched the novel seed compounds among adamantane derivatives with blocking action of KATP channels. We successfully discovered novel adamantane derivative, TP-compound X targeting for KATP channels, which is more potent than memantine. In the pharmacological examination, we confirmed that TP-compound improves both cognitive deficits via Kir6.2 channel inhibition and behavioral and psychological symptoms of dementia (BPSD) such as depressive-like behaviors, anxiety-like behaviors and aggressive-like behaviors via Kir6.1 channel inhibition in mice.

  6. Functional significance of target molecule of cognitive enhancer ST101 and drug development

    Fukunaga Kohji, FUKUDA TAKAICHI, MORIGUCHI SHIGEKI

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (B)

    Institution: Tohoku University

    2013/04/01 - 2016/03/31

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    After structure optimization of ST101 as cognitive enhancer, we developed the novel spiro-imidazopyridine derivative, SAK3. Oral administration of SAK3 (0.5mg/kg) enhanced hippocampal acetylcholine release through T-type calcium channels. In olfactory bulbectomized mice, oral administration of SAK3 improved cognitive function by activation of Ca2+/calmodulin-dependent protein kinase II (CaMKII) in the hippocampus. We next treated Alzheimer model mice APP23 with SAK3 (0.5mg/kg) for three months. The SAK3 treatment inhibited amyloid beat protein accumulation, thereby improving cognitive dysfunction. We also established evaluation protocol of pharmacodynamics after oral administration in rats. Overall, we conduct preclinical studies of SAK3 for safety and pharmacodynamic properties.

  7. Drug discovery study of Alzheimer's disease target for T-type calcium channel activation

    MORIGUCHI Shigeki

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (C)

    Institution: Tohoku University

    2012/04/01 - 2015/03/31

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    We developed a novel cognitive enhancer, ST101 that activates T-type voltage-gated calcium channels (VGCCs). Here, we address whether T-type VGCC activation with ST101 mediates its cognitive effects in vivo and the relevance of T-type VGCC activation to acetylcholine release in the hippocampus. Acute administration of ST101 at 1 mg/kg, i.p. improved memory-related behaviors in olfactory bulbectomized (OBX) mice. Effects of ST101 administration were abolished by pre-administration of the T-type VGCC inhibitor mibefradil. As expected, significantly reduced CaMKIIα, PKCα, and ERK phosphorylation was restored by acute ST101 administration in the OBX mouse hippocampal CA1 region. Enhancement of CaMKIIα and PKCα but not ERK phosphorylation was inhibited by mibefradil. Taken together, stimulation of T-type VGCCs is critical for the enhanced hippocampal ACh release and improved cognitive function seen following ST101 administration.

  8. Drug development targeting for regeneration of neurovascular units in neurodegenerative disorders

    FUKUNAGA Kohji, IWABUCHI Yoshiharu, ITO Yoshihisa, MORIGUCHI Shigaki

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (B)

    Institution: Tohoku University

    2010 - 2012

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    ST101 stimulates memory molecule, Ca2+/calmodulin-dependent protein kinase II (CaMKII) in the hippocampus. In the present study, we investigated whether chronic administration of the neurovascular regenerative compound, ST101 elicits long lasting ameliorating effects on brain functions and defined the molecular mechanism underlying their therapeutic effects in the neurodegenerative disorders. ST101 was now under investigation in Phase II clinical trial of U.S.A. We defined T type voltage-gated calcium channel as molecular target of ST101. We next introduced novel and potent derivative, SAK3 by using neuro2A cells overexpressing T type voltage-gated calcium channel. This is the first discovery of activators of T type voltage-gated calcium channel in the world. The most promising evidence in our studies is that T type calcium channel is novel therapeutic target of Alzheimer therapy to restore the neural networks in the neurodegenerative disorders.

  9. Development of Alzheimer's disease therapeutics mediate for enhancement of synaptic transmission

    MORIGUCHI Shigeki

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Young Scientists (B)

    Institution: Tohoku University

    2010 - 2011

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    Sunifiram is a new pyrrolidone nootropic drug structurally related to piracetam, being development for neurodegenerative disorder like Alzheimer's disease. Sunifiram modulates glycine binding site of NMDAR concomitant increased PKC・activity through Src family kinase. Enhancement of PKC・activity triggered to potentiates hippocampal LTP through activation of CaMKII.

  10. Role of fatty acid-binding protein in the brain vulnerability in schizophrenia

    FUKUNAGA Kohji, MORIGUCHI Shigeki

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Challenging Exploratory Research

    Institution: Tohoku University

    2010 - 2011

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    H-FABP is associated with D2L receptor in vivo. H-FABP null mice showed increased anxiety and impaired cognitive behavior. The impaired cognitive behavior was associated with decreased CaMKII activities in the cingulate cortex and DHA diet improved the impaired cognitive behaviors in H-FABP null mice. Thus, the decreased CaMKII activity likely mediates impairments of cognitive function in H-FABP null mice. H-FABP null mice are useful to define the role of FABP in the vulnerable of schizophrenia brain.

  11. Effect of cognitive function mediated by NMDA receptor activation of new nootropic drug.

    MORIGUCHI Shigeki

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Young Scientists (B)

    Institution: Tohoku University

    2008 - 2009

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    In this present study, we demonstrated that nefiracetam mediates cognitive function through activation of CaM kinase II (Moriguchi et al., J. Neurochem. 2008), and nefiracetam augments the impairment of coginitive function through activation of CaM kinase II and PKC in olfactory bulbectomized mice (Moriguchi et al., J. Neurochem. 2009), and nefiracetam enhances glutamatergic system via presynaptic nicotinic acethylcholine receptors in rat cortical neurons (Moriguchi et al., Neuroscinece 2009), and galantamine mediates cognitive function through activation of CaM kinase II (Moriguchi et al., Hippocampus, 2009).

  12. Development of novel neuroprotective drugs targeting for neurovascular unit therapy.

    FUKUNAGA Kohji, IWABUCHI Yushiharu, MORIOKA Motohiro, KASAHARA Jiro, MORIGUCHI Shigeki, SHIODA Norifumi

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (B)

    Institution: Tohoku University

    2007 - 2009

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    We have introduced novel neuroprotective drugs including calmodulin antagonist DY-9760e and protein kinase B (Akt) activator VO (OPT) in the ischemic neurodegeneration. However, the mechanisms underlying neurovascular unit protection by these compounds remain unclear. We found that DY-9760e and its active metabolite, DY-9836 are potent inhibitors of calcium/calmodulin dependent nitric oxide synthase (NOS) in vivo. We here defined pathophysiological role and mechanism of superoxide generation through uncoupled eNOS in phenylephrine (PE)-induced hypertrophic cardiomyocytes. In PE-induced hypertrophic cardiomyocytes, the superoxide generation was associated with increased uncoupling state of eNOS. Thus, uncoupling of eNOS accounts for superoxide generation by prolonged PE exposure, thereby inducing apoptotic cell death. Furthermore, cardioprotective effects of DY-9836 well correlated with inhibition of aberrant superoxide generation by suppression of eNOS activity. DY-9836 treatment also protected cardiomyocytes from breakdown of caveolin-3/dystrophin, which are major components to scaffold eNOS in cardiomyocyte caveolae. Similarly, DY-9836 treatment also attenuated superoxide generation following brain ischemia by uncoupled eNOS in vascular endothelial cells. Thus the inhibition of superoxide production by DY-9760e/DY9836 is critical for protection of neurovascular units in ischemia-induced neurodegenaration. Neurogenesis is well documented in the subgranular zone (SGZ) of hippocampus. Especially, in the hippocampal neurogenesis, fundamental role of neurogenesis in learning and memory formation has been addressed. We here assessed whether VO (OPT), a stimulator of phosphatidylinositol 3-kinase (PI3K)/Akt and extracellular signal regulated kinase (ERK) pathways promotes neurogenesis following brain ischemia using a mouse transient middle cerebral artery occlusion (MCAO) model. Intraperitoneal administrations of VO (OPT), which is a potent inhibitor for protein tyrosine phosphatases (PTPs), stimulated neurogenesis in the adult dentate gyrus (DG) following brain ischemia. VO (OPT) led to activation of PI3K/Akt and ERK pathways, which are inhibited by treatment with specific inhibitor, wortmannin or U-0126, respectively. Each treatment of them significantly inhibited the neurogenesis, suggesting that both pathways need to elicit VO (OPT)-induced neurogenesis following brain ischemia. In some behavioral studies, we showed that VO (OPT)-induced neurogenesis accounts for improvement of memory deficits following brain ischemia. These results suggest that intraperitoneal administrations of VO (OPT) stimulate neurogenesis following brain ischemia through PI3K/Akt and ERK activation. Moreover, Akt- and ERK-induced neurogenesis is critical for improvement of memory deficits following brain ischemia.

  13. NMDA受容体グリシン結合部位を標的とした新規アルツハイマー病治療薬の創薬研究

    森口 茂樹

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 若手研究(B)

    Institution: 東北大学

    2006 - 2007

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    申請者はこれまでアルツハイマー病治療薬として承認を受けているdonepezil、galantamineにアセチルコリン賦活作用だけでなく、NMDA受容体賦活作用を有することを見出した。さらに、アルツハイマー病治療薬の候補化合物であるピロリドン誘導体であるnefiracetamも同様に、ニコチン性アセチルコリン受容体賦活作用だけでなく、NMDA受容体賦活作用を有することを見出した。本研究では、nefiracetamの細胞内機序ならびにシナプス間隙におけnefiracetamの作用部位について電気生理学的解析、ならびに生化学的解析を行った。その結果、nefiracetamは細胞内においてprotein kinase C (PKC)の活性化を介してNMDA受容体を活性化していること(Moriguchi et al., Mol. Pharmacol. 2007)、nefiracetamはシナプス前終末においてニコチン性アセチルコリン受容体の活性化を介してグルタミン酸の遊離を促進していること(Moriguchi etal., JPET under submission)、さらに後シナプスにおいて細胞内のCa2+/calmodulin-dependent protein kinase II(CaMKII)およびPKCの活性化を引き起こすこと(Moriguchi et al., J. Neurochem. Under revision)を見出した。本研究より、新しいアルツハイマー病治療薬の作用機序として、NMDA受容体賦活作用ならびに細胞内CaMKIIおよびPKCの活性化が重要であることが明らかとなり、今後、より詳細な検討を行う予定である。

  14. 小胞体機能異常による細胞内カルシウムシグナルと記憶学習の障害

    森口 茂樹, 福永 浩司, 塩田 倫史

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 特定領域研究

    Institution: 東北大学

    2006 - 2007

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    申請者は、小胞体機能を担うジャンクトフィリン遺伝子欠損マウスの解析の結果、ジャンクトフィリン遺伝子欠損マウスでは、認知機能の有意な低下が認められ、その細胞内機序として神経細胞の活動電位における再分極機構であるAfterhyperpolarization(AHP)の機能異常ならびにカルシウム活性型カリウムチャンネル(SK channel)の異常により、認知機能の低下が惹起されていること、さらに、細胞内で認知機能と密接に関与しているカルシウム/カルモデュリン依存性プロテインキナーゼII(CaMKII)の活性異常が認められ、小胞体機能異常が誘発されると、細胞内のカルシウム恒常性の異常が起こり、認知機能の獲得に異常が認められることを明らかとした。申請者の最近の研究により、小胞体機能異常と統合失調症との関与についても新しい知見を得た。覚醒剤であるメタンフェタミンを慢性的に実験動物に投与すると、経日的な異常行動、すなわち行動逆耐性が誘発する。しかしながら、ジャンクトフィリン遺伝子欠損マウスでは、行動逆耐性の誘発は認められない。情動行動に関与する線条体においてシナプス可塑性の変化について電気生学的検討を行った結果、皮質-線条体に投射するグルタミン酸シナプスにおいて、通常見出される長期抑圧現象(LTD)がジャンクトフィリン遺伝子欠損マウスでは認められなかった。さらに、メタンフェタミンは線条体の細胞内CaMKIIの活性を低下させるが、ジャンクトフィリン遺伝子欠損マウスではCaMKIIの活性の低下は認められなかった。すなわち、小胞体機能による細胞内カルシウム調節が行動逆耐性の誘発に関与する可能性が示唆された。本研究により、新しい認知機能ならびに統合失調症の細胞内機序の確立を行った。今後、小胞体機能異常により様々な病態との関与について検討を行う予定である。

  15. アダマンタンアミン類の精密構造修飾に基づく高特異的イオンチャネルブロック薬の創製

    岩渕 好治, 森口 茂樹, 澁谷 正俊

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 萌芽研究

    Institution: 東北大学

    2005 - 2006

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    昨年度までの研究から、アダマンタンアミノ酸、アダマンタンアミン類が中枢神経グルタミン酸受容体に対してアンタゴニストおよびアゴニスト活性を惹起することを明らかとした。そこで、本年度はリード化合物としているad001の構造活性相関研究を行うとともに多様なアダマンタン誘導体の中枢神経活性評価を行った。 海馬CaMキナーゼII活性を指標とした神経薬理活性評価法の確立 これまで行ってきた電気生理学的手法は詳細な薬理活性評価を可能とするが、煩雑な操作を要するため多数の化合物の迅速な評価は困難であった。そこで、多様なアダマンタン誘導体の簡便な薬理活性評価法を確立するため検討を行った結果、海馬CaMキナーゼII活性を指標とした方法を確立できた。本法で得た結果は電気生理学的手法で得た結果と良い相関を示した。 アタマンタン誘導体中枢神経活性化合物の探索 上記薬効評価法を用いて、新たに合成した約40種類のアダマンタン誘導体の活性評価を行った。その結果、中枢神経活性を有する約10種類のアダマンタン誘導体を獲得した。 リード化合物ad001の構造活性相関 NMDA受容体アンタゴニスト活性を有するad001のα-アミノ酸部、2つの水酸基が、このものの活性に及ぼす影響を調べる目的で、アミノ酸部の立体化学逆のR配置の誘導体、2つの水酸基をもたないアミノ酸、5位の水酸基を持たないアミノ酸をそれぞれ合成し、薬理活性評価を行った。その結果、アミノ酸部がR配置のアダマンタンアミノ酸はより強い抑制活性を示し、2つの水酸基の有無も活性発現に必須であることが明らかとなった。本年度の研究においてad001の構造のわずかな違いが活性発現に大きく影響することがわか明らかとなった。

  16. デルタ型CaMキナーゼIIの中枢ドパミン神経可塑性における役割

    福永 浩司, 森口 茂樹, 塩田 倫史

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 特定領域研究

    Institution: 東北大学

    2005 - 2005

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    哺乳動物の認知機能に関与する神経回路と神経可塑性研究に比べて、注意、意欲、情動に関与する神経回路発達と神経可塑性研究は遅れている。私達はドパミン受容体を介する新しいシグナル伝達を見出した。即ち、cAMPを介するシグナル伝達に加えて、ドパミン受容体はD1およびD2受容体ともに細胞内カルシウム動員系を活性化する。その結果、カルシウム/カルモデュリン(CaM)依存性プロテインキナーゼII(CaMKII)とカルシニューリンを活性化することが解った。特に、D2受容体の刺激はCaMKIIを活性化して脳由来神経栄養因子(BDNF)の発現を亢進させた。一方、カルシニューリンもD2受容体刺激で活性化され、MAPキナーゼであるERKを介して、転写因子NF-κBを活性化した。これらのことはD2受容体はGi蛋白質を介して、D1受容体シグナル伝達を抑制するのに加えて、カルシウム系を活性化して神経細胞の生存に関わることを示唆している。D2受容体は自己受容体として黒質、腹側被蓋野のドパミン神経に発現している。黒質ドパミン神経にγA、γC、δ1、δ3型のCaMKIIが発現することを見出した。特にδ3アイソフォームは黒質の核内に存在してBDNFの発現に関与していた。また、D2受容体の細胞膜発現に対してCaMKIIが促進的に働くことを見出した。これらのBDNF発現によるドパミン神経の生存と、D2受容体の神経活動依存的な細胞膜局在化の生理機能を解明するために黒質ドパミン神経に恒常的活性型CaMKIIを過剰に発現する遺伝子改変マウスを作成した。行動解析とドパミン神経の神経可塑性の解析からドパミン神経におけるCaMKIIの生理機能をさらに追究する。

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Media Coverage 7

  1. アルツハイマー病の新薬 効く仕組み解明 脳の糖尿病説実証

    河北新報

    2016/11/22

    Type: Newspaper, magazine

  2. 脳細胞つなぎ役 壊れると物忘れ

    朝日新聞

    2006/06/29

    Type: Newspaper, magazine

  3. 記憶のコツは休息

    読売新聞

    2006/06/27

    Type: Newspaper, magazine

  4. 記憶に必須タンパク質を解明

    産經新聞

    2006/06/27

    Type: Newspaper, magazine

  5. 脳神経細胞のたんぱく質 記憶に重要な役割

    毎日新聞

    2006/06/27

    Type: Newspaper, magazine

  6. 記憶学習に安息期必要

    京都新聞

    2006/06/27

    Type: Newspaper, magazine

  7. 記憶に重要な働き たんぱく質を発見

    日本経済新聞

    2006/06/27

    Type: Newspaper, magazine

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