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  2. Taku Nagai

Taku Nagai

  (永井 拓)

Profile Information

Affiliation
Professor, Division of Behavioral Neuropharmacology, International Center for Brain Science (ICBS), Fujita Health University
(Concurrent)Vice Director, International Center for Brain Science (ICBS)
(Concurrent)Professor, Department of Behavioral Neuropharmacology, Graduate School of Medicine
(Concurrent)Vice Director, Open Facility Center
Degree
M.S.(Meijo University)
Ph.D.(Nagoya University)
J-GLOBAL ID
200901083965882198
researchmap Member ID
5000081871

Research Interests

 7

Research Areas

 1

Research History

 5

Committee Memberships

 14
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Awards

 10
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Papers

 187
  • Youyun Zhu, Kanako Kitagawa, Daisuke Mori, Tetsuo Matsuzaki, Taku Nagai, Toshitaka Nabeshima, Sayaka Takemoto-Kimura, Hiroaki Ikesue, Norio Ozaki, Hiroyuki Mizoguchi, Kiyofumi Yamada
    European Journal of Pharmacology, Jan, 2026  
  • Hisayoshi Kubota, Xinjian Zhang, Masoumeh Khalili, Xinzhu Zhou, Yu Wen, Taku Nagai
    International Journal of Molecular Sciences, May 28, 2025  
  • Masaya Hasegawa, Kazuo Kunisawa, Bolati Wulaer, Hisayoshi Kubota, Hitomi Kurahashi, Takatoshi Sakata, Honomi Ando, Suwako Fujigaki, Hidetsugu Fujigaki, Yasuko Yamamoto, Taku Nagai, Kuniaki Saito, Toshitaka Nabeshima, Akihiro Mouri
    British Journal of Pharmacology, Dec 10, 2024  
    Background and Purpose Alterations in tryptophan‐kynurenine (TRP‐KYN) pathway are implicated in major depressive disorder (MDD). α7 nicotinic acetylcholine (α7nACh) receptor regulates the hypothalamic–pituitary–adrenal (HPA) axis. We have shown that deficiency of kynurenine 3‐monooxygenase (KMO) induces depression‐like behaviour via kynurenic acid (KYNA; α7nACh antagonist). In this study, we investigated the involvement of the TRP‐KYN pathway in stress‐induced behavioural changes and the regulation of the HPA axis. Experimental Approach Mice were exposed to chronic unpredictable mild stress (CUMS) and subjected to behavioural tests. We measured TRP‐KYN metabolites and the expression of their enzymes in the hippocampus. KMO heterozygous mice were used to investigate stress vulnerability. We also evaluated the effect of nicotine (s.c.) on CUMS‐induced behavioural changes and an increase in serum corticosterone (CORT) concentration. Key Results CUMS decreased social interaction time but increased immobility time under tail suspension associated with increased serum corticosterone concentration. CUMS increased KYNA levels via KMO suppression with microglial decline in the hippocampus. Kmo+/− mice were vulnerable to stress: they exhibited social impairment and increased serum corticosterone concentration even after short‐term CUMS. Nicotine attenuated CUMS‐induced behavioural changes and increased serum corticosterone concentration by inhibiting the increase in corticotropin‐releasing hormone. Methyllycaconitine (α7nACh antagonist) inhibited the attenuating effect of nicotine. Conclusions and Implications CUMS‐induced behavioural changes and the HPA axis dysregulation could be induced by the increased levels of KYNA via KMO suppression. KYNA plays an important role in the pathophysiology of MDD as an α7nACh antagonist. Therefore, α7nACh receptor is an attractive therapeutic target for MDD.
  • Hitomi Kurahashi, Kazuo Kunisawa, Kenji F. Tanaka, Hisayoshi Kubota, Masaya Hasegawa, Mai Miyachi, Yuka Moriya, Yoichi Hasegawa, Taku Nagai, Kuniaki Saito, Toshitaka Nabeshima, Akihiro Mouri
    Neuropsychopharmacology, Oct 11, 2024  
    Abstract Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by repetitive behaviors, social deficits, and cognitive impairments. Maternal use of valproic acid (VPA) during pregnancy is associated with an increased risk of ASD in offspring. The prevailing pathophysiological hypothesis for ASD involves excitation/inhibition (E/I) imbalances and serotonergic dysfunction. Here, we investigated the association between glutamatergic-serotonergic neuronal interactions and ASD-like behaviors in mice exposed to prenatal VPA. Prenatal VPA exposure induced excessive repetitive self-grooming behavior and impaired social behavior and object recognition memory in young adult period. Prenatal VPA mice showed hyper-glutamatergic function (increase in basal extracellular glutamate levels and CaMKII phosphorylation) and hypo-serotonergic function (decrease in 5-hydroxyindoleacetic acid and stimulation-induced serotonin [5-HT] release, but an increase in 5-HT transporter expression) in the prefrontal cortex. Treatment with a low-affinity NMDA receptor antagonist (memantine), a selective 5-HT reuptake inhibitor (fluoxetine), and a 5-HT1A receptor agonist (tandospirone) attenuated both the increase in CaMKII phosphorylation and ASD-like behavior of prenatal VPA mice. Opto-genetic activation of the serotonergic neuronal system attenuated impairments in social behavior and object recognition memory in prenatal VPA mice. WAY-100635—a 5-HT1A receptor antagonist—antagonized the effect of fluoxetine on impaired social behavior and object recognition memory. These results suggest that E/I imbalance and ASD-like behavior are associated with hypo-serotonergic receptor signaling through 5-HT1A receptors in prenatal VPA mice.
  • Yasuhiro Funahashi, Rijwan Uddin Ahammad, Xinjian Zhang, Emran Hossen, Masahiro Kawatani, Shinichi Nakamuta, Akira Yoshimi, Minhua Wu, Huanhuan Wang, Mengya Wu, Xu Li, Md Omar Faruk, Md Hasanuzzaman Shohag, You-Hsin Lin, Daisuke Tsuboi, Tomoki Nishioka, Keisuke Kuroda, Mutsuki Amano, Yukihiko Noda, Kiyofumi Yamada, Kenji Sakimura, Taku Nagai, Takayuki Yamashita, Shigeo Uchino, Kozo Kaibuchi
    Science signaling, 17(853) eado9852, Sep 10, 2024  
    Structural plasticity of dendritic spines in the nucleus accumbens (NAc) is crucial for learning from aversive experiences. Activation of NMDA receptors (NMDARs) stimulates Ca2+-dependent signaling that leads to changes in the actin cytoskeleton, mediated by the Rho family of GTPases, resulting in postsynaptic remodeling essential for learning. We investigated how phosphorylation events downstream of NMDAR activation drive the changes in synaptic morphology that underlie aversive learning. Large-scale phosphoproteomic analyses of protein kinase targets in mouse striatal/accumbal slices revealed that NMDAR activation resulted in the phosphorylation of 194 proteins, including RhoA regulators such as ARHGEF2 and ARHGAP21. Phosphorylation of ARHGEF2 by the Ca2+-dependent protein kinase CaMKII enhanced its RhoGEF activity, thereby activating RhoA and its downstream effector Rho-associated kinase (ROCK/Rho-kinase). Further phosphoproteomic analysis identified 221 ROCK targets, including the postsynaptic scaffolding protein SHANK3, which is crucial for its interaction with NMDARs and other postsynaptic scaffolding proteins. ROCK-mediated phosphorylation of SHANK3 in the NAc was essential for spine growth and aversive learning. These findings demonstrate that NMDAR activation initiates a phosphorylation cascade crucial for learning and memory.
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Misc.

 242
  • 張 心健, 貝淵 弘三, 永井 拓
    ファルマシア, 60(11) 1030-1034, Nov 1, 2024  Peer-reviewedInvited
  • 船橋靖広, 船橋靖広, AHAMMAD Rijwan Uddin, AHAMMAD Rijwan Uddin, 張心健, EMRAN Hossen, EMRAN Hossen, 河谷昌泰, 吉見陽, 吉見陽, 呉敏華, 王緩緩, 王緩緩, 坪井大輔, 坪井大輔, 西岡朋生, 西岡朋生, 黒田啓介, 天野睦紀, 野田幸裕, 野田幸裕, 山田清文, 崎村建司, 永井拓, 山下貴之, 内野茂夫, 貝淵弘三, 貝淵弘三
    日本薬理学雑誌, 158(Supplement), 2023  
  • 松﨑 哲郎, 奥村 啓樹, 永井 拓, 山田 清文
    日本アルコール・薬物医学会雑誌, 56(2) 31-38, Apr, 2021  
  • Bolati Wulaer, Kazuo Kunisawa, Kazuhiro Hada, Willy Jaya Suento, Hisayoshi Kubota, Tsubasa Iida, Aika Kosuge, Taku Nagai, Kiyofumi Yamada, Atsumi Nitta, Yasuko Yamamoto, Kuniaki Saito, Akihiro Mouri, Toshitaka Nabeshima
    Journal of neurochemistry, 157(3) 642-655, Apr 10, 2020  
    Successful completion of daily activities relies on the ability to select the relevant features of the environment for memory and recall. Disruption to these processes can lead to various disorders, such as attention-deficit hyperactivity disorder (ADHD). Dopamine is a neurotransmitter implicated in the regulation of several processes, including attention. In addition to the higher-order brain function, dopamine is implicated in the regulation of adult neurogenesis. Previously, we generated mice lacking Shati, an N-acetyltransferase-8-like protein on a C57BL/6J genetic background (Shati/Nat8l-/- ). These mice showed a series of changes in the dopamine system and ADHD-like behavioral phenotypes. Therefore, we hypothesized that deficiency of Shati/Nat8l would affect neurogenesis and attentional behavior in mice. We found aberrant morphology of neurons and impaired neurogenesis in the dentate gyrus of Shati/Nat8l-/- mice. Additionally, research has suggested that impaired neurogenesis might be because of the reduction of dopamine in the hippocampus. Galantamine (GAL) attenuated the attentional impairment observed in the object-based attention test via increasing the dopamine release in the hippocampus of Shati/Nat8l-/- mice. The α7 nicotinic acetylcholine receptor antagonist, methyllycaconitine, and dopamine D1 receptor antagonist, SCH23390, blocked the ameliorating effect of GAL on attentional impairment in Shati/Nat8l-/- mice. These results suggest that the ameliorating effect of GAL on Shati/Nat8l-/- attentional impairment is associated with activation of D1 receptors following increased dopamine release in the hippocampus via α7 nicotinic acetylcholine receptor. In summary, Shati/Nat8l is important in both morphogenesis and neurogenesis in the dentate gyrus and attention, possible via modulation of dopaminergic transmission.
  • Yukako Nakamura, Masahiro Nakatochi, Shohko Kunimoto, Takashi Okada, Branko Aleksic, Miho Toyama, Tomoko Shiino, Mako Morikawa, Aya Yamauchi, Akira Yoshimi, Yoko Furukawa-Hibi, Taku Nagai, Masako Ohara, Chika Kubota, Kiyofumi Yamada, Masahiko Ando, Norio Ozaki
    BMC psychiatry, 19(1) 190-190, Jun 20, 2019  
    BACKGROUND: Postpartum depression (PPD) is a major depressive disorder that occurs after childbirth. Objective diagnostic and predictive methods for PPD are important for early detection and appropriate intervention. DNA methylation has been recognized as a potential biomarker for major depressive disorder. In this study, we used methylation analysis and peripheral blood to search for biomarkers that could to lead to the development a predictive method for PPD. METHODS: Study participants included 36 pregnant women (18 cases and 18 controls determined after childbirth). Genome-wide DNA methylation profiles were obtained by analysis with an Infinium Human Methylation 450BeadChip. The association of DNA methylation status at each DNA methylation site with PPD was assessed using linear regression analysis. We also conducted functional enrichment analysis of PPD using The Database for Annotation, Visualization and Integrated Discovery 6.8 to explore enriched functional-related gene groups for PPD. RESULTS: In the analysis with postpartum depressed state as an independent variable, the difference in methylation frequency between the postpartum non-depressed group and the postpartum depressed group was small, and sites with genome-wide significant differences were not confirmed. After analysis by The Database for Annotation, Visualization and Integrated Discovery 6.8, we revealed four gene ontology terms, including axon guidance, related to postpartum depression. CONCLUSIONS: These findings may help with the development of an objective predictive method for PPD.
  • Akira Yoshimi, Shinnosuke Yamada, Shohko Kunimoto, Branko Aleksic, Akihiro Hirakawa, Mitsuki Ohashi, Yurie Matsumoto, Kazuhiro Hada, Norimichi Itoh, Yuko Arioka, Hiroki Kimura, Itaru Kushima, Yukako Nakamura, Tomoko Shiino, Daisuke Mori, Satoshi Tanaka, Shuko Hamada, Yukihiro Noda, Taku Nagai, Kiyofumi Yamada, Norio Ozaki
    Translational psychiatry, 9(1) 126-126, Apr 22, 2019  
    Although a number of studies have identified several convincing candidate genes or molecules, the pathophysiology of schizophrenia (SCZ) has not been completely elucidated. Therapeutic optimization based on pathophysiology should be performed as early as possible to improve functional outcomes and prognosis; to detect useful biomarkers for SCZ, which reflect pathophysiology and can be utilized for timely diagnosis and effective therapy. To explore biomarkers for SCZ, we employed fluorescence two-dimensional differential gel electrophoresis (2D-DIGE) of lymphoblastoid cell lines (LCLs) (1st sample set: 30 SCZ and 30 CON). Differentially expressed proteins were sequenced by liquid chromatography tandem-mass spectrometry (LC-MS/MS) and identified proteins were confirmed by western blotting (WB) (1st and 2nd sample set: 60 SCZ and 60 CON). Multivariate logistic regression analysis was performed to identify an optimal combination of biomarkers to create a prediction model for SCZ. Twenty protein spots were differentially expressed between SCZ and CON in 2D-DIGE analysis and 22 unique proteins were identified by LC-MS/MS. Differential expression of eight of 22 proteins was confirmed by WB. Among the eight candidate proteins (HSPA4L, MX1, GLRX3, UROD, MAPRE1, TBCB, IGHM, and GART), we successfully constructed logistic regression models comprised of 4- and 6-markers with good discriminative ability between SCZ and CON. In both WB and gene expression analysis of LCL, MX1 showed reproducibly significant associations. Moreover, Mx1 and its related proinflamatory genes (Mx2, Il1b, and Tnf) were also up-regulated in poly I:C-treated mice. Differentially expressed proteins might be associated with molecular pathophysiology of SCZ, including dysregulation of immunological reactions and potentially provide diagnostic and prognostic biomarkers.
  • 祖父江 顕, 永井 拓, 山田 清文
    ストレス科学, 33(3) 233-241, Mar, 2019  
  • Xinjian Zhang, Taku Nagai, Rijwan Uddin Ahammad, Keisuke Kuroda, Shinichi Nakamuta, Takashi Nakano, Naoto Yukinawa, Yasuhiro Funahashi, Yukie Yamahashi, Mutsuki Amano, Junichiro Yoshimoto, Kiyofumi Yamada, Kozo Kaibuchi
    Neurochemistry international, 122 8-18, Jan, 2019  Peer-reviewed
    Medium spiny neurons (MSNs) expressing dopamine D1 receptor (D1R) or D2 receptor (D2R) are major components of the striatum. Stimulation of D1R activates protein kinase A (PKA) through Golf to increase neuronal activity, while D2R stimulation inhibits PKA through Gi. Adenosine A2A receptor (A2AR) coupled to Golf is highly expressed in D2R-MSNs within the striatum. However, how dopamine and adenosine co-operatively regulate PKA activity remains largely unknown. Here, we measured Rap1gap serine 563 phosphorylation to monitor PKA activity and examined dopamine and adenosine signals in MSNs. We found that a D1R agonist increased Rap1gap phosphorylation in striatal slices and in D1R-MSNs in vivo. A2AR agonist CGS21680 increased Rap1gap phosphorylation, and pretreatment with the D2R agonist quinpirole blocked this effect in striatal slices. D2R antagonist eticlopride increased Rap1gap phosphorylation in D2R-MSNs in vivo, and the effect of eticlopride was blocked by the pretreatment with the A2AR antagonist SCH58261. These results suggest that adenosine positively regulates PKA in D2R-MSNs through A2AR, while this effect is blocked by basal dopamine in vivo. Incorporating computational model analysis, we propose that the shift from D1R-MSNs to D2R-MSNs or vice versa appears to depend predominantly on a change in dopamine concentration.
  • 永井 拓, 祖父江 顕, 久島 周, 尾崎 紀夫, 山田 清文
    日本臨床精神神経薬理学会・日本神経精神薬理学会合同年会プログラム・抄録集, 28回・48回 131-131, Nov, 2018  
  • 永井 拓, 祖父江 顕, 山田 清文
    ストレス科学, 33(2) 132-132, Oct, 2018  
  • Md Ali Bin Saifullah, Taku Nagai, Keisuke Kuroda, Bolati Wulaer, Toshitaka Nabeshima, Kozo Kaibuchi, Kiyofumi Yamada
    Scientific reports, 8(1) 14413-14413, Sep 26, 2018  Peer-reviewed
    Medium spiny neurons (MSN) in the nucleus accumbens (NAc) are a fundamental component of various aspects of motivated behavior. Although mitogen-activated protein kinase (MAPK) signaling plays a crucial role in several types of learning, the cell type-specific role of MAPK pathway in stimulus-reward learning and motivation remains unclear. We herein investigated the role of MAPK in accumbal MSNs in reward-associated learning and memory. During the acquisition of Pavlovian conditioning, the number of phosphorylated MAPK1/3-positive cells was increased significantly and exclusively in the NAc core by 7-days of extensive training. MAPK signaling in the respective D1R- and D2R-MSNs was manipulated by transfecting an adeno-associated virus (AAV) plasmid into the NAc of Drd1a-Cre and Drd2-Cre transgenic mice. Potentiation of MAPK signaling shifted the learning curve of Pavlovian conditioning to the left only in Drd1a-Cre mice, whereas such manipulation in D2R-MSNs had negligible effects. In contrast, MAPK manipulation in D2R-MSNs of the NAc core significantly increased motivation for food rewards as found in Drd1a-Cre mice. These results suggest that MAPK signaling in the D1R-MSNs of NAc core plays an important role in stimulus-reward learning, while MAPK signaling in both D1R- and D2R-MSNs is involved in motivation for natural rewards.
  • Akira Sobue, Itaru Kushima, Taku Nagai, Wei Shan, Takao Kohno, Branko Aleksic, Yuki Aoyama, Daisuke Mori, Yuko Arioka, Naoko Kawano, Maeri Yamamoto, Mitsuharu Hattori, Toshitaka Nabeshima, Kiyofumi Yamada, Norio Ozaki
    Scientific reports, 8(1) 13046-13046, Aug 29, 2018  Peer-reviewed
    Reelin protein (RELN), an extracellular matrix protein, plays multiple roles that range from embryonic neuronal migration to spine formation in the adult brain. Results from genetic studies have suggested that RELN is associated with the risk of psychiatric disorders, including schizophrenia (SCZ). We previously identified a novel exonic deletion of RELN in a patient with SCZ. High-resolution copy number variation analysis revealed that this deletion included exons 52 to 58, which truncated the RELN in a similar manner to the Reln Orleans mutation (Relnrl-Orl). We examined the clinical features of this patient and confirmed a decreased serum level of RELN. To elucidate the pathophysiological role of the exonic deletion of RELN in SCZ, we conducted behavioral and neurochemical analyses using heterozygous Relnrl-Orl/+ mice. These mice exhibited abnormalities in anxiety, social behavior, and motor learning; the deficits in motor learning were ameliorated by antipsychotics. Methamphetamine-induced hyperactivity and dopamine release were significantly reduced in the Relnrl-Orl/+ mice. In addition, the levels of GABAergic markers were decreased in the brain of these mice. Taken together, our results suggest that the exonic deletion of RELN plays a pathological role, implicating functional changes in the dopaminergic and GABAergic systems, in the pathophysiology of SCZ.
  • Imai, K, Kotani, T, Tsuda, H, Nakano, T, Ushida, T, Iwase, A, Nagai T, Toyokuni, S, Suzumura, A, Kikkawa, F
    Sci Rep, 8(1) 9221-9221, Jun 15, 2018  Peer-reviewed
    The aim of the present study was to investigate long-term outcomes of the offspring in a lipopolysaccharide (LPS)-induced maternal immune activation (MIA) model and the effect of maternal molecular hydrogen (H2) administration. We have previously demonstrated in the MIA mouse model that maternal administration of H2 attenuates oxidative damage and neuroinflammation, including induced pro-inflammatory cytokines and microglial activation, in the fetal brain. Short-term memory, sociability and social novelty, and sensorimotor gating were evaluated using the Y-maze, three-chamber, and prepulse inhibition (PPI) tests, respectively, at postnatal 3 or 4 weeks. The number of neurons and oligodendrocytes was also analyzed at postnatal 5 weeks by immunohistochemical analysis. Offspring of the LPS-exposed dams showed deficits in short-term memory and social interaction, following neuronal and oligodendrocytic loss in the amygdala and cortex. Maternal H2 administration markedly attenuated these LPS-induced abnormalities. Moreover, we evaluated the effect of H2 on LPS-induced astrocytic activation, both in vivo and in vitro. The number of activated astrocytes with hypertrophic morphology was increased in LPS-exposed offspring, but decreased in the offspring of H2-administered dams. In primary cultured astrocytes, LPS-induced pro-inflammatory cytokines were attenuated by H2 administration. Overall, these findings indicate that maternal H2 administration exerts neuroprotective effects and ameliorates MIA-induced neurodevelopmental deficits of offspring later in life.
  • Akira Sobue, Norimichi Ito, Taku Nagai, Wei Shan, Kazuhiro Hada, Akira Nakajima, Yuki Murakami, Akihiro Mouri, Yasuko Yamamoto, Toshitaka Nabeshima, Kuniaki Saito, Kiyofumi Yamada
    Glia, 66(5) 1034-1052, May, 2018  
    In the central nervous system, major histocompatibility complex class I (MHCI) molecules are mainly expressed in neurons, and neuronal MHCI have roles in synapse elimination and plasticity. However, the pathophysiological significance of astroglial MHCI remains unclear. We herein demonstrate that MHCI expression is up-regulated in astrocytes in the medial prefrontal cortex (mPFC) following systemic immune activation by an intraperitoneal injection of polyinosinic-polycytidylic acid (polyI:C) or hydrodynamic interferon (IFN)-γ gene delivery in male C57/BL6J mice. In cultured astrocytes, MHCI/H-2D largely co-localized with exosomes. To investigate the role of astroglial MHCI, H-2D, or sH-2D was expressed in the mPFC of male C57/BL6J mice using an adeno-associated virus vector under the control of a glial fibrillary acidic protein promoter. The expression of astroglial MHCI in the mPFC impaired sociability and recognition memory in mice. Regarding neuropathological changes, MHCI expression in astrocytes significantly activated microglial cells, decreased parvalbumin-positive cell numbers, and reduced dendritic spine density in the mPFC. A treatment with GW4869 that impairs exosome synthesis ameliorated these behavioral and neuropathological changes. These results suggest that the overexpression of MHCI in astrocytes affects microglial proliferation as well as neuronal numbers and spine densities, thereby leading to social and cognitive deficits in mice, possibly via exosomes created by astrocytes.
  • Wulaer, B, Nagai T, Sobue, A, Itoh, N, Kuroda, K, Kaibuchi, K, Nabeshima, T, Yamada, K
    Gene Brain Behav, e12478, Apr 10, 2018  Peer-reviewed
  • Wei Shan, Taku Nagai, Motoki Tanaka, Norimichi Itoh, Yoko Furukawa-Hibi, Toshitaka Nabeshima, Masahiro Sokabe, Kiyofumi Yamada
    Journal of Neurochemistry, 145(1) 19-33, Apr 1, 2018  
  • Masahito Sawahata, Kanako Kitagawa, Yumi Tsuneura, Taku Nagai, Takao Kohno, Toshitaka Nabeshima, Mitsuharu Hattori, Kiyofumi Yamada
    Proceedings for Annual Meeting of The Japanese Pharmacological Society, {WCP}2018 PO1-1, 2018  
  • Norimichi Itoh, Taku Nagai, Takashi Watanabe, Kentaro Taki, Toshitaka Nabeshima, Kozo Kaibuchi, Kiyofumi Yamada
    Biochemical and biophysical research communications, 493(4) 1384-1389, Dec 2, 2017  Peer-reviewed
    Scaffold proteins play a pivotal role in making protein complexes, and organize binding partners into a functional unit to enhance specific signaling pathways. IQ motif-containing GTPase activating protein 1 (IQGAP1) is an essential protein for spine formation due to its role in scaffolding multiple signal complexes. However, it remains unclear how IQGAP1 interacts within the brain. In the present study, we screened novel IQGAP1-interacting proteins by a proteomic approach. As a novel IQGAP1-interacting protein, we identified valosin-containing protein (VCP) which is a causative gene in patients with inclusion body myopathy with Paget's disease of bone and frontotemporal dementia (IBMPFD). The physiological interaction of IQGAP1 with VCP was confirmed by an immunoprecipitation assay. Both the N-terminal (N-half) and C-terminal (C-half) fragments of IQGAP1 interacted with the N-terminal region of VCP. Co-localization of IQGAP1 and VCP was observed in the growth corn, axonal shaft, cell body, and dendrites in cultured hippocampal neurons at 4 days in vitro (DIV4). In cultured neurons at DIV14, IQGAP1 co-localized with VCP in dendrites. When HEK293T cells were co-transfected with IQGAP1 and VCP, an immunoprecipitation assay revealed that binding of IQGAP1 with disease-related mutant (R155H or A232E) VCP was markedly reduced compared to wild-type (WT) VCP. These results suggest that reduction of IQGAP1 and VCP interaction may be associated with the pathophysiology of IBMPFD.
  • 祖父江 顕, 伊藤 教道, 羽田 和弘, 中島 晶, 村上 由希, 毛利 彰宏, 山本 康子, 鍋島 俊隆, 齋藤 邦明, 永井 拓, 山田 清文
    日本生物学的精神医学会・日本神経精神薬理学会合同年会プログラム・抄録集, 39回・47回 193-193, Sep, 2017  
  • D. Tsuboi, T. Shimomura, T. Nakano, T. Nagai, M. Amano, J. Yoshimoto, Y. Kubo, K. Kaibuchi
    JOURNAL OF NEUROCHEMISTRY, 142 135-135, Aug, 2017  
  • Y. Funahashi, A. Ariza, K. Suzuki, S. Wei, S. Kozawa, T. Takano, K. Kuroda, T. Nagai, K. Kaibuchi
    JOURNAL OF NEUROCHEMISTRY, 142 129-129, Aug, 2017  
  • Hiroyuki Konishi, Nobutaka Ohgami, Aika Matsushita, Yuki Kondo, Yuki Aoyama, Masaaki Kobayashi, Taku Nagai, Shinya Ugawa, Akiyofumi Yamada, Masashi Kato, Hiroshi Kiyama
    NEUROSCIENCE, 351 15-23, May, 2017  Peer-reviewed
  • Akira Sobue, Norimichi Ito, Kazuhiro Hada, Akira Nakajima, Toshitaka Nabeshima, Taku Nagai, Kiyofumi Yamada
    JOURNAL OF PHARMACOLOGICAL SCIENCES, 133(3) S177-S177, Mar, 2017  
  • 祖父江顕, 伊藤教道, 単偉, 羽田和弘, 中島晶, 村上由希, 毛利彰宏, 山本康子, 鍋島俊隆, 鍋島俊隆, 齋藤邦明, 永井拓, 山田清文
    日本薬理学会近畿部会プログラム・要旨集, 131st 34, 2017  
  • Kubo, K.I, Deguchi, K, Nagai T, Ito, Y, Yoshida, K, Endo, T, Benner, S, Shan, W, Kitazawa, A, Aramaki, M, Ishii, K, Shin, M, Matsunaga, Y, Hayashi, K, Kakeyama, M, Tohyama, C, Tanaka, K.F, Tanaka, K, Takashima, S, Nakayama, M, Itoh, M, Hirata, Y, Antalffy, B, Armstrong, D.D, Yamada, K, Inoue, K, Nakajima, K
    JCI Insight., 2(10) pii: 88609, 2017  Peer-reviewed
    Many extremely preterm infants (born before 28 gestational weeks [GWs]) develop cognitive impairment in later life, although the underlying pathogenesis is not yet completely understood. Our examinations of the developing human neocortex confirmed that neuronal migration continues beyond 23 GWs, the gestational week at which extremely preterm infants have live births. We observed larger numbers of ectopic neurons in the white matter of the neocortex in human extremely preterm infants with brain injury and hypothesized that altered neuronal migration may be associated with cognitive impairment in later life. To confirm whether preterm brain injury affects neuronal migration, we produced brain damage in mouse embryos by occluding the maternal uterine arteries. The mice showed delayed neuronal migration, ectopic neurons in the white matter, altered neuronal alignment, and abnormal corticocortical axonal wiring. Similar to human extremely preterm infants with brain injury, the surviving mice exhibited cognitive deficits. Activation of the affected medial prefrontal cortices of the surviving mice improved working memory deficits, indicating that decreased neuronal activity caused the cognitive deficits. These findings suggest that altered neuronal migration altered by brain injury might contribute to the subsequent development of cognitive impairment in extremely preterm infants.
  • Masaaki Tanino, Motomu Kobayashi, Toshihiro Sasaki, Ken Takata, Yoshimasa Takeda, Satoshi Mizobuchi, Kiyoshi Morita, Taku Nagai, Hiroshi Morimatsu
    ACTA MEDICA OKAYAMA, 70(6) 455-460, Dec, 2016  Peer-reviewed
  • Taku Nagai, Junichiro Yoshimoto, Takayuki Kannon, Keisuke Kuroda, Kozo Kaibuchi
    Trends in pharmacological sciences, 37(10) 858-871, Oct, 2016  Peer-reviewedInvited
    Dopamine signaling in the brain is a complex phenomenon that strongly contributes to emotional behaviors. Medium spiny neurons (MSNs) play a major role in dopamine signaling through dopamine D1 receptors (D1Rs) or dopamine D2 receptors (D2Rs) in the striatum. cAMP/protein kinase A (PKA) regulates phosphorylation signals downstream of D1Rs, which affects the excitability of MSNs, leading to reward-associated emotional expression and memory formation. A combination of phosphoproteomic approaches and the curated KANPHOS database can be used to elucidate the physiological and pathophysiological functions of dopamine signaling and other monoamines. Emerging evidence from these techniques suggests that the Rap1 pathway plays a crucial role in the excitability of MSNs, leading to the expression of emotional behaviors.
  • Kiyofumi Yamada, Akira Sobue, Yuki Aoyama, Shan Wei, Taku Nagai, Branko Aleksic, Itaru Kushima, Norio Ozaki
    INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY, 19 185-185, Jun, 2016  
  • 祖父江 顕, 伊藤 教道, 羽田 和弘, 中島 晶, 永井 拓, 鍋島 俊隆, 山田 清文
    応用薬理, 90(5-6) 149-149, Jun, 2016  
  • 羽田 和弘, 伊藤 教道, 祖父江 顕, 鍋島 俊隆, 永井 拓, 山田 清文
    応用薬理, 90(5-6) 165-165, Jun, 2016  
  • Xinjian Zhang, Keisuke Kuroda, Hiroyuki Takenaka, Kaishu Oda, Reon Kondo, Tomoki Nishioka, Shinichi Nakamuta, Taku Nagai, Kozo Kaibuchi
    JOURNAL OF PHARMACOLOGICAL SCIENCES, 130(3) S194-S194, Mar, 2016  
  • Taku Nagai, Shinichi Nakamuta, Keisuke Kuroda, Sakura Nakauchi, Tomoki Nishioka, Tetsuya Takano, Xinjian Zhang, Daisuke Tsuboi, Yasuhiro Funahashi, Takashi Nakano, Junichiro Yoshimoto, Kenta Kobayashi, Motokazu Uchigashima, Masahiko Watanabe, Masami Miura, Akinori Nishi, Kazuto Kobayashi, Kiyofumi Yamada, Mutsuki Amano, Kozo Kaibuchi
    Neuron, 89(3) 550-65, Feb 3, 2016  Peer-reviewed
    Dopamine (DA) type 1 receptor (D1R) signaling in the striatum presumably regulates neuronal excitability and reward-related behaviors through PKA. However, whether and how D1Rs and PKA regulate neuronal excitability and behavior remain largely unknown. Here, we developed a phosphoproteomic analysis method to identify known and novel PKA substrates downstream of the D1R and obtained more than 100 candidate substrates, including Rap1 GEF (Rasgrp2). We found that PKA phosphorylation of Rasgrp2 activated its guanine nucleotide-exchange activity on Rap1. Cocaine exposure activated Rap1 in the nucleus accumbens in mice. The expression of constitutively active PKA or Rap1 in accumbal D1R-expressing medium spiny neurons (D1R-MSNs) enhanced neuronal firing rates and behavioral responses to cocaine exposure through MAPK. Knockout of Rap1 in the accumbal D1R-MSNs was sufficient to decrease these phenotypes. These findings demonstrate a novel DA-PKA-Rap1-MAPK intracellular signaling mechanism in D1R-MSNs that increases neuronal excitability to enhance reward-related behaviors.
  • 19(1) 18-22,3, 2016  
  • Kenzo Hirao, Kei Eto, Yoshihisa Nakahata, Hitoshi Ishibashi, Taku Nagai, Junichi Nabekura
    Journal of neurophysiology, 114(3) 1974-86, Sep, 2015  
    Neuronal circuit plasticity during development is fundamental for precise network formation. Pioneering studies of the developmental visual cortex indicated that noradrenaline (NA) is crucial for ocular dominance plasticity during the critical period in the visual cortex. Recent research demonstrated tonotopic map formation by NA during the critical period in the auditory system, indicating that NA also contributes to synaptic plasticity in this system. The lateral superior olive (LSO) in the auditory system receives glutamatergic input from the ventral cochlear nucleus (VCN) and undergoes circuit remodeling during postnatal development. LSO is innervated by noradrenergic afferents and is therefore a suitable model to study the function of NA in refinement of neuronal circuits. Chemical lesions of the noradrenergic system and chronic inhibition of α2-adrenoceptors in vivo during postnatal development in mice disrupted functional elimination and strengthening of VCN-LSO afferents. This was potentially mediated by activation of presynaptic α2-adrenoceptors and inhibition of glutamate release because NA presynaptically suppressed excitatory postsynaptic current (EPSC) through α2-adrenoceptors during the first two postnatal weeks in an in vitro study. Furthermore, NA and α2-adrenoceptor agonist induced long-term suppression of EPSCs and decreased glutamate release. These results suggest that NA has a critical role in synaptic refinement of the VCN-LSO glutamatergic pathway through failure of synaptic transmission. Because of the ubiquitous distribution of NA afferents and the extensive expression of α2-adrenoceptors throughout the immature brain, this phenomenon might be widespread in the developing central nervous system.
  • Yoko Furukawa-Hibi, Taku Nagai, Jaesuk Yun, Kiyofumi Yamada
    NEUROREPORT, 26(14) 827-832, Sep, 2015  Peer-reviewed
  • Akira Nakajima, Yuki Aoyama, Eun-Joo Shin, Yunsung Nam, Hyoung-Chun Kim, Taku Nagai, Akihito Yokosuka, Yoshihiro Mimaki, Tsuyoshi Yokoi, Yasushi Ohizumi, Kiyofumi Yamada
    BEHAVIOURAL BRAIN RESEARCH, 289 69-77, Aug, 2015  Peer-reviewed
  • Kazuhiro Ishii, Taku Nagai, Yuki Hirota, Mariko Noda, Toshitaka Nabeshima, Kiyofumi Yamada, Ken-ichiro Kubo, Kazunori Nakajima
    NEUROSCIENCE RESEARCH, 96 30-36, Jul, 2015  Peer-reviewed
  • Tsuyoshi Udagawa, Yusuke Fujioka, Motoki Tanaka, Daiyu Honda, Satoshi Yokoi, Yuichi Riku, Daisuke Ibi, Taku Nagai, Kiyofumi Yamada, Hirohisa Watanabe, Masahisa Katsuno, Toshifumi Inada, Kinji Ohno, Masahiro Sokabe, Haruo Okado, Shinsuke Ishigaki, Gen Sobue
    Nature communications, 6 7098-7098, May 13, 2015  Peer-reviewed
    FUS is an RNA/DNA-binding protein involved in multiple steps of gene expression and is associated with amyotrophic lateral sclerosis (ALS) and fronto-temporal lobar degeneration (FTLD). However, the specific disease-causing and/or modifying mechanism mediated by FUS is largely unknown. Here we evaluate intrinsic roles of FUS on synaptic functions and animal behaviours. We find that FUS depletion downregulates GluA1, a subunit of AMPA receptor. FUS binds GluA1 mRNA in the vicinity of the 3' terminus and controls poly (A) tail maintenance, thus regulating stability. GluA1 reduction upon FUS knockdown reduces miniature EPSC amplitude both in cultured neurons and in vivo. FUS knockdown in hippocampus attenuates dendritic spine maturation and causes behavioural aberrations including hyperactivity, disinhibition and social interaction defects, which are partly ameliorated by GluA1 reintroduction. These results highlight the pivotal role of FUS in regulating GluA1 mRNA stability, post-synaptic function and FTLD-like animal behaviours.
  • Aoyama, Y, Toriumi, K, Mouri, A, Hattori, T, Ueda, E, Shimato, A, Sakakibara, N, Soh, Y, Mamiya, T, Nagai, T, Kim, H.-C, Hiramatsu, M, Nabeshima, T, Yamada, K
    Neuropsychopharmacology, 46回 96-96, 2015  Peer-reviewed
  • Mizoguchi, Hiroyuki, Katahira, Kentaro, Inutsuka, Ayumu, Fukumoto, Kazuya, Nakamura, Akihiro, Wang, Tian, Nagai, Taku, Sato, Jun, Sawada, Makoto, Ohira, Hideki, Yamanaka, Akihiro, Yamada, Kiyofumi
    Proceedings of the National Academy of Sciences of the United States of America, 112(29) E3930-39309, 2015  Peer-reviewed
  • Kei Hori, Taku Nagai, Wei Shan, Asami Sakamoto, Shinichiro Taya, Ryoya Hashimoto, Takashi Hayashi, Manabu Abe, Maya Yamazaki, Keiko Nakao, Tomoki Nishioka, Kenji Sakimura, Kiyofumi Yamada, Kozo Kaibuchi, Mikio Hoshino
    CELL REPORTS, 9(6) 2166-2179, Dec, 2014  
  • Akira Nakajima, Daisuke Ibi, Taku Nagai, Shinnosuke Yamada, Toshitaka Nabeshima, Kiyofumi Yamada
    EUROPEAN JOURNAL OF PHARMACOLOGY, 745 166-175, Dec, 2014  Peer-reviewed
  • Tsuyoshi Nakai, Taku Nagai, Motoki Tanaka, Norimichi Itoh, Naoya Asai, Atsushi Enomoto, Masato Asai, Shinnosuke Yamada, Ali Bin Saifullah, Masahiro Sokabe, Masahide Takahashi, Kiyofumi Yamada
    JOURNAL OF NEUROSCIENCE, 34(45) 14995-15008, Nov, 2014  Peer-reviewed
  • Hiroshi Kato, Masayuki Miyazaki, Mio Takeuchi, Naoto Sassa, Taku Nagai, Yukihiro Noda, Kiyofumi Yamada
    ANNALS OF ONCOLOGY, 25, Oct, 2014  
  • Sei-ichi Yoshihara, Hiroo Takahashi, Nobushiro Nishimura, Masahito Kinoshita, Ryo Asahina, Michiko Kitsuki, Kana Tatsumi, Yoko Furukawa-Hibi, Hirokazu Hirai, Taku Nagai, Kiyofumi Yamada, Akio Tsuboi
    CELL REPORTS, 8(3) 843-857, Aug, 2014  Peer-reviewed
  • Tsuyoshi Nakai, Taku Nagai, Rui Wang, Shinnosuke Yamada, Keisuke Kuroda, Kozo Kaibuchi, Kiyofumi Yamada
    NEUROCHEMISTRY INTERNATIONAL, 74 74-83, Jul, 2014  Peer-reviewed
  • A. Yoshimi, S. Kunimoto, S. Yamada, B. Aleksic, A. Hirakawa, T. Nagai, N. Ozaki
    INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY, 17 119-119, Jun, 2014  
  • Shinnosuke Yamada, Taku Nagai, Tsuyoshi Nakai, Daisuke Ibi, Akira Nakajima, Kiyofumi Yamada
    BRAIN BEHAVIOR AND IMMUNITY, 38 272-282, May, 2014  Peer-reviewed
  • Tokiko Morita, Koji Senzaki, Ryoko Ishihara, Kazunori Umeda, Nakao Iwata, Taku Nagai, Hirotake Hida, Toshitaka Nabeshima, Kazunori Yukawa, Norio Ozaki, Yukihiro Noda
    HUMAN PSYCHOPHARMACOLOGY-CLINICAL AND EXPERIMENTAL, 29(3) 280-286, May, 2014  Peer-reviewed
  • Yukio Mano, Tomomi Kotani, Mikako Ito, Taku Nagai, Yuko Ichinohashi, Kiyofumi Yamada, Kinji Ohno, Fumitaka Kikkawa, Shinya Toyokuni
    FREE RADICAL BIOLOGY AND MEDICINE, 69 324-330, Apr, 2014  Peer-reviewed

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  • 統合失調症マーカー及びその利用, 尾崎紀夫, 永井拓, 吉見陽, 山田真之亮.「国立大学法人名古屋大学, 特許番号6252949, 出願番号 特願 2014-542025, 管理番号 C20130185JP#P01, 出願日2013.10.3., 特許取得2017.12.8.
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