HOME > Members > GCOE Organizing Members > Kiyofumi Yamada PhD

Kiyofumi Yamada PhDProfessor, Department of Clinical Pharmacy, Nagoya University Graduate School of Medicine

Specialized field

Pharmaceutical Sciences

Career Summary

1981 B.S.
Meijo University, Nagoya, Japan
1983 M.S.
Pharmacology, Meijo University, Nagoya, Japan
1991 Ph.D.
Pharmacology, Meijo University, Nagoya, Japan
Position Held:
Research Scientist, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan
Visiting Scientist, Department of Neuroscience, The Johns Hopkins University School of Medicine (Prof. Joseph T. Coyle)
Clinical Pharmacist, Department of Hospital Pharmacy, Nagoya University School of Medicine
Associate Professor and Vice Director, Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine
Professor and Chairman, Laboratory of Neuropsychopharmacology, Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Kanazawa University
Professor and Chairman, Laboratory of Neuropsychopharmacology, Division of Life Sciences, Graduate School of Natural Science and Technology, Kanazawa University
Professor and Director, Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine

Research Theme

Neuropharmacological study on the development of novel drugs in neuropsychiatric disorders

Research Summary

Neuropharmacological study on the development of novel drugs in neuropsychiatric disorders

In the research supported by the G-COE program, we focus on the neuropharmacological study to develop novel drugs in neuropsychiatric disorders such as schizophrenia. Interactions of environmental and genetic factors may play a role in the pathoetiology of schizophrenia. Some potential environmental insults, such as viral infection and stress during the developmental stage could affect brain development. We have previously demonstrated that neonatal injection of polyriboinosinic-polyribocytidylic acid (polyI:C) in ICR mice, which elicits a strong innate immune response, induces schizophrenia-like behavioral alterations with an impairment of glutamate release in the hippocampus in adulthood. We suggested that the induction of IFITM3 in astrocytes during the early neonatal period might play a crucial role in neurodevelopmental disturbance induced by polyI:C treatment. Furthermore, we have reported a novel animal model for schizophrenia by inducing abnormal immune response with polyI:C treatment during the perinatal period in transgenic mice with human dominant-negative form of disrupted-in-schizophrenia 1. Besides, we identified neuronal PAS domain 4 (Npas4) as a stress-responsible transcription factor that regulates neuronal function. In 2011, we investigated the role of IFITM3 in astroglial cells. Furthermore, we investigated the role of Npas4 in neurodevelopment and neuropsychological function.

1. Role of IFITM3 in astroglial cells
IFITM3 in polyI:C-treated astrocytes and COS7 cells transfected with myc-Ifitm3 colocalized exclusively with early endosomal antigen 1 (EEA1), an established early endosome marker. IFITM3 immunoreactivity in polyI:C-treated cultured astrocytes was not observed in other organelles. Because of the selective localization of IFITM3 in the early endosomes of astrocytes, we speculated that IFITM3 might modulate their function, i.e., endocytosis. Endocytosis consists of two different systems, namely, clathrin-dependent and -independent. Accordingly, we analyzed the uptake of Alexa Fluor 555-labeled transferrin (AF555-Tf) and epidermal growth factor (AF555-EGF) in Ifitm3-transfected COS7 cells as a measure of clathrin-dependent and -independent endocytosis, respectively. AF555-Tf and AF555-EGF uptake in Ifitm3-transfected COS7 cells was significantly reduced compared to their uptake in control and MOCK-transfected COS7 cells. In contrast, Ifitm3 overexpression in COS7 cells had no effect on AF555-Tf recycling. To confirm the effect of IFITM3 on endocytosis in cultured astrocytes, AF555-Tf and AF555-EGF uptake was measured in polyI:C-treated wt and Ifitm3-KO astrocytes. PolyI:C treatment markedly reduced AF555-Tf and AF555-EGF uptake in wt astrocytes. The reduction of AF555-EGF uptake was completely abolished in Ifitm3-KO astrocytes, while AF555-Tf uptake was partially reversed in Ifitm3-KO astrocytes. These results suggest that IFITM3 overexpression in the early endosomes following polyI:C treatment impair endocytic activity in astrocytes, which may underlie the polyI:C-induced impairments of neurodevelopment (Fig. 1).

2. Role of NPAS4 in neurodevelopment and neuropsychological function
KCl treatment increased dendritic length and complexity in WT hippocampal neurons, but not in Npas4-KO hippocampal neurons. We confirmed the increase in Npas4 protein levels after KCl stimulation in primary hippocampal neurons. The binding of NPAS4 to the promoters of Npas4 and Cdk5 was proven by the ChIP assay. We investigated if p-Syn I expression was affected by in vivo pentylenetetrazole (PTZ) treatment in WT and Npas4-KO mice because it has been reported that PTZ-induced convulsions in mice lead to an increase in the Npas4 mRNA level in the hippocampus. PTZ administration increased NPAS4 levels in the prefrontal cortex of WT mice, but not in Npas4-KO mice. p-Syn I levels were increased by PTZ administration in WT mice while the same treatment had no effect on p-Syn I levels in Npas4-KO mice. There was no difference in the intensity score of convulsions induced by PTZ treatment between Npas4-KO mice and WT mice, suggesting that the changes in p-Syn I levels after PTZ treatment in Npas4-KO mice are not due to the reduced excitability of neurons in the mutant mice. Behavioral analysis revealed that Npas4-KO mice showed abnormalities in emotional behaviors, sensorimotor gating function and hippocampus-dependent memories in the elevated-plus maze test, prepulse inhibition test and fear conditioning test, respectively. These results suggest that activity-dependent induction of NPAS4 plays a crucial role in neurodevelopment and neuropsychological function (Fig. 2).

Principal Research Achievement

  1. Mouri A, Sasaki A, Watanabe K, Sogawa C, Kitayama S, Mamiya T, Miyamoto Y, Yamada K, Noda Y, Nabeshima T: MAGE-D1 Regulates Expression of Depression-Like Behavior through Serotonin Transporter Ubiquitylation. J Neurosci, 32, 4562-4580 (2012)
  2. Takuma K, Mizoguchi H, Funatsu Y, Hoshina Y, Himeno Y, Fukuzaki E, Kitahara Y, Arai S, Ibi D, Kamei H, Matsuda T, Koike K, Inoue M, Nagai T, Yamada K: Combination of chronic stress and ovariectomy causes conditioned fear memory deficits and hippocampal cholinergic neuronal loss in mice. Neuroscience, 207, 261-273 (2012)
  3. Tran HY, Shin EJ, Saito K, Nguyen XK, Chung YH, Jeong JH, Bach JH, Park DH, Yamada K, Nabeshima T, Yoneda Y, Kim HC: Protective potential of IL-6 against trimethyltin-induced neurotoxicity in vivo. Free Radic Biol Med, 52, 1159-1174 (2012)
  4. Alkam T, Hiramatsu M, Mamiya T, Aoyama Y, Nitta A, Yamada K, Kim HC, Nabeshima T: Evaluation of object-based attention in mice. Behav Brain Res, 220, 185-193 (2011)
  5. Furukawa-Hibi Y, Alkam T, Nitta A, Matsuyama A, Mizoguchi H, Suzuki K, Moussaoui S, Yu QS, Greig NH, Nagai T, Yamada K: Butyrylcholinesterase inhibitors ameliorate cognitive dysfunction induced by amyloid-beta peptide in mice. Behav Brain Res, 225, 222-229 (2011)
  6. Furukawa-Hibi Y, Nitta A, Ikeda T, Morishita K, Liu W, Ibi D, Alkam T, Nabeshima T, Yamada K: The hydrophobic dipeptide Leu-Ile inhibits immobility induced by repeated forced swimming via the induction of BDNF. Behav Brain Res, 220, 271-280 (2011)
  7. Ibi D, Nagai T, Nabeshima T, Yamada K: PolyI:C-induced neurodevelopmental animal model for schizophrenia. Nihon Shinkei Seishin Yakurigaku Zasshi, 31, 201-207 (2011)
  8. Kuroda K, Yamada S, Tanaka M, Iizuka M, Yano H, Mori D, Tsuboi D, Nishioka T, Namba T, Iizuka Y, Kubota S, Nagai T, Ibi D, Wang R, Enomoto A, Isotani-Sakakibara M, Asai N, Kimura K, Kiyonari H, Abe T, Mizoguchi A, Sokabe M, Takahashi M, Yamada K, Kaibuchi K: Behavioral alterations associated with targeted disruption of exons 2 and 3 of the Disc1 gene in the mouse. Hum Mol Genet, 20, 4666-4683 (2011)
  9. Mizoguchi H, Ibi D, Takase F, Nagai T, Kamei H, Toth E, Sato J, Takuma K, Yamada K: Nicotine ameliorates impairment of working memory in methamphetamine-treated rats. Behav Brain Res, 220, 159-163 (2011)
  10. Mizoguchi H, Nakade J, Tachibana M, Ibi D, Someya E, Koike H, Kamei H, Nabeshima T, Itohara S, Takuma K, Sawada M, Sato J, Yamada K: Matrix metalloproteinase-9 contributes to kindled seizure development in pentylenetetrazole-treated mice by converting pro-BDNF to mature BDNF in the hippocampus. J Neurosci, 31, 12963-12971 (2011)
  11. Mizoguchi H, Yamada K: Pharmacologic Treatment with GABA(B) Receptor Agonist of Methamphetamine-Induced Cognitive Impairment in Mice. Curr Neuropharmacol, 9, 109-112 (2011)
  12. Nagai T, Ibi D, Yamada K: Animal model for schizophrenia that reflects gene-environment interactions. Biol Pharm Bull, 34, 1364-1368 (2011)
  13. Nagai T, Kitahara Y, Ibi D, Nabeshima T, Sawa A, Yamada K: Effects of antipsychotics on the behavioral deficits in human dominant-negative DISC1 transgenic mice with neonatal polyI:C treatment. Behav Brain Res, 225, 305-310 (2011)
  14. Shichi K, Fujita-Hamabe W, Harada S, Mizoguchi H, Yamada K, Nabeshima T, Tokuyama S: Involvement of matrix metalloproteinase-mediated proteolysis of neural cell adhesion molecule in the development of cerebral ischemic neuronal damage. J Pharmacol Exp Ther, 338, 701-710 (2011)
  15. Shin EJ, Kim JM, Nguyen X-K T, Nguyen T-T L, Lee S Y, Jung J-H, Kim M J, Whang W K, Yamada K, Nabeshima T, Kim H-C: Effects of Gastrodia Bl on Phencycline-Induced Schizophrenia-Like psychosis in Mice. Curr Neuropharmacol, 9, 247-250 (2011)
  16. Lu P, Mamiya T, Lu L, Mouri A, Niwa M, Kim HC, Zou L B, Nagai T, Yamada K, Ikejima T, Nabeshima T: Silibinin attenuates cognitive deficits and decreases of dopamine and serotonin induced by repeated methamphetamine treatment. Behav Brain Res, 207, 387-393 (2010)
  17. Tsuritani K, Takeda J, Sakagami J, Ishii A, Eriksson T, Toshifumi Hara T, Ishibashi H, Koshihara Y, Yamada K, Yoneda Y: Cytokine receptor-like factor 1 is highly expressed in damaged human knee OA cartilage and is involved in OA downstream of TGF-β. Calcif Tissue Int, 86, 47-57 (2010)
  18. Alkam T, Nitta A, Furukawa-Hibi Y, Niwa M, Mizoguchi H, Yamada K, Nabeshima T: Oral supplementation with Leu-Ile, a hydrophobic dipeptide, prevents the impairment of memory induced by amyloid beta in mice via restraining the hyperphosphorylation of extracellular signal-regulated kinase. Behav Brain Res, 210, 184-190 (2010)
  19. Noda Y, Mouri A, Ando Y, Waki Y, Yamada SN, Yoshimi A, Yamada K, Ozaki N, Wang D, Nabeshima T: Galantamine ameliorates the impairment of recognition memory in mice repeatedly treated with methamphetamine: involvement of allosteric potentiation of nicotinic acetylcholine receptors and dopaminergic-ERK1/2 systems. Int J Neuropsychopharmacol, 11, 1-12 (2010)
  20. Katsuno M, Adachi H, Minamiyama M, Waza M, Doi H, Kondo N, Mizoguchi H, Nitta A, Yamada K, Banno H, Suzuki K, Tanaka F, Sobue G: Disrupted transforming growth factor-beta signaling in spinal and bulbar muscular atrophy. J Neurosci, 30, 5702-5712 (2010)
  21. Yun J, Koike H, Ibi D, Toth E, Mizoguchi H, Nitta A, Yoneyama M, Ogita K, Yoneda Y, Nabeshima T, Nagai T, Yamada K: Chronic restraint stress impairs neurogenesis and hippocampus-dependent fear memory in mice: possible involvement of a brain-specific transcription factor Npas4. J Neurochem, 114, 1840-1851 (2010)
  22. Yu J, Nagai T, Ibi D, Kitahara Y, Nabeshima T, Yamada K: Nicotine ameliorates emotional and cognitive impairments induced by neonatal polyI:C treatment in mice. Open Behav Sci J, 4, 9-18 (2010)
  23. Mizoguchi H, Ibi D, Takuma K, Toth E, Sato J, Itohara S, Nabeshima N, Yamada K: Alterations of emotional and cognitive behaviors in matrix metalloproteinase-2 and -9-deficient mice. Open Behav Sci J, 4, 19-25 (2010)
  24. Furukawa-Hibi Y, Nitta A, Fukumitsu Y, Somiya H, Furukawa S, Nabeshima T, Yamada K: Overexpression of piccolo C2A domain induces depression-like behavior in mice. Neuroreport, 21, 1177-1181 (2010)
  25. Nagai T, Kitahara Y, Shiraki A, Hikita T, Taya S, Kaibuchi K, Yamada K. Dysfunction of dopamine release in the prefrontal cortex of dysbindin deficient sandy mice: An in vivo microdialysis study. Neurosci Lett, 470, 134-138 (2010)
  26. Ibi D, Nagai T, Koike H, Kitahara Y, Mizoguchi H, Niwa M, Hanna Jaaro-Peled, Nitta A, Yoneda Y, Nabeshima T, Sawa A, Yamada Y. Combined effect of neonatal immune activation and mutant DISC1 on phenotypic changes in adulthood. Behav Brain Res, 206, 32-37 (2010)
  27. Mizoguchi H, Arai S, Koike H, Ibi D, Kamei H, Nabeshima T, Kim HC, Takuma K, Yamada K. Therapeutic potential of nicotine for methamphetamine-induced impairment of sensorimotor gating: involvement of pallidotegmental neurons. Psychopharmacology, 207, 235-243 (2009)
  28. Takuma K, Fang F, Zhang W, Yan S, Fukuzaki E, Du H, Sosunov A, McKhann G, Funatsu Y, Nakamichi N, Nagai T, Mizoguchi H, Ibi D, Hori O, Ogawa S, Stern DM, Yamada K, Yan SS. RAGE-mediated signaling contributes to intraneuronal transport of amyloid-{beta} and neuronal dysfunction. Proc Natl Acad Sci USA, 106, 20021-20026 (2009)
  29. Koike H, Ibi D, Mizoguchi H, Nagai T, Nitta A, Takuma K, Nabeshima T, Yoneda Y, Yamada K. Behavioral abnormality and pharmacologic response in social isolation-reared mice. Behav Brain Res, 202, 114?121 (2009)
  30. Mizoguchi H, Takuma K, Fukuzaki E, Ibi D, Someya E, Akazawa KH, Alkam T, Tsunekawa H, Mouri A, Noda Y, Nabesima T, Yamada K. Matrix metalloprotease-9 inhibition improves amyloid{beta}-mediated cognitive impairment and neurotoxicity in mice. J Phamacol Exp Ther, 331, 14-22 (2009)
  31. Ibi D, Nagai T, Kitahara Y, Mizoguchi H, Koike H, Shiraki A, Takuma K, Kamei H, Noda Y, Nitta A, Nabeshima T, Yoneda Y, Yamada K. Neonatal polyI:C treatment in mice results in schizophrenia-like behavioral and neurochemical abnormalities in adulthood. Neurosci Res, 64, 297-305 (2009)
  32. Arai S, Takuma K, Mizoguchi H, Ibi D, Nagai T, Kamei H, Kim HC, Yamada K. GABAB receptor agonist baclofen improves methamphetamine-induced cognitive deficit in mice. Eur J Pharmacol, 602, 101-104 (2009)
  33. Mizoguchi H, Takuma K, Fukakusa A, Ito Y, Nakatani A, Ibi D, Kim HC, Yamada K. Improvement by minocycline of methamphetamine-induced impairment of recognition memory in mice. Psychopharmacology (Berl), 196, 233-241 (2008)
  34. Fukuzaki E, Takuma K, Himeno Y, Yoshida S, Funatsu Y, Kitahara Y, Mizoguchi H, Ibi D, Koike K, Inoue M, Yamada K. Enhanced activity of hippocampal BACE1 in a mouse model of postmenopausal memory deficits. Neurosci Lett, 433, 141-145 (2008)
  35. Arai S, Takuma K, Mizoguchi H, Ibi D, Nagai T, Takahashi K, Kamei H, Nabeshima T, Yamada K. Involvement of pallidotegmental neurons in methamphetamine- and MK-801-induced impairment of prepulse inhibition of the acoustic startle reflex in mice: reversal by GABAB receptor agonist baclofen. Neuropsychopharmacology, 33, 3164-3175, (2008)
  36. Fukuzaki E, Takuma K, Funatsu Y, Himeno Y, Kitahara Y, Gu B, Mizoguchi H, Ibi D, Koike K, Inoue M, Yan SD, Yamada K. Ovariectomy increases neuronal amyloid β binding alchohol dehydrogenease level in the mouse hippocampus. Neurochem Int, 52, 1358-1364, (2008)
  37. Alkam T, Nitta A, Mizoguchi H, Itoh A, Murai R, Nagai T, Yamada K, Nabeshima T. The extensive nitration of neurofilament light chain in the hippocampus is associated with the cognitive impairment induced by amyloid β in mice. J Pharmacol Exp Ther, 327, 137-147 (2008)
  38. Ibi D, Takuma K, Koike H, Mizoguchi H, Tsuritani K, Kuwahara Y, Kamei H, Nagai T, Yoneda Y, Nabeshima T, Yamada K. Social isolation rearing-induced impairment of the hippocampal neurogenesis is associated with deficits in spatial memory and emotion-related behaviors in juvenile mice. J Neurochem, 105, 921-932 (2008)
  39. Fukakusa A, Nagai T, Mizoguchi H, Otsuka N, Kimura H, Kamei H, Kim H-C, Nabeshima T, Takuma K, Yamada K. Role of tissue plasminogen activator in the sensitization of methamphetamine-induced dopamine release in the nucleus accumbens. J Neurochem, 105, 436-444 (2008)
  40. Yijin Y et al. Enduring vulnerability to reinstatement of methamphetamine-seeking behavior in glial cell line-derived neurotrophic factor mutant mice. FASEB J. 21: 1994-2004 (2007)
  41. Jin D et al. CD38 is critical for social behavior by regulating oxytocin secretion. Nature 446: 41-45 (2007)
  42. Takahashi K et al. Neural circuits containing pallidotegmental GABAergic neurons are involved in the prepulse inhibition of the startle reflex in mice. Biol. Psychiatry 62: 148-157 (2007)
  43. Nagai T et al. The rewards of nicotine: regulation by tissue plasminogen activator-plasmin system through protease activated receptor-1. J. Neurosci. 26: 12374-12383 (2006)
  44. Kamei H et al. Repeated methamphetamine treatment impairs recognition memory through a failure of novelty-induced ERK 1/2 activation in the prefrontal cortex. Biol. Psychiatry 59: 75-84 (2006)
  45. Matsuoka Y et al. Prostaglandin E receptor EP1 controls impulsive behavior under stress. Proc. Natl. Acad. Sci. USA 102: 16066-16071 (2005)
  46. Nagai T et al. Tissue plasminogen activator-plasmin system participates in the rewarding effect of morphine by regulating dopamine release. Proc. Natl. Acad. Sci. USA 101: 3650-3655 (2004)
  47. Nakajima A et al. Role of TNF-a in methamphetamine-induced drug dependence and neurotocicity. J. Neurosci. 24: 2212-2225 (2004)
  48. Mamiya T et al. Neuronal mechanism of nociceptin-induced modulation of learning and memory: Involvement of N-methyl-D-aspartate receptors. Mol. Psychiatry 8: 752-765 (2003)
  49. Nagai T et al. Cognition impairment in the genetic model of aging, klotho gene mutant mice: a role of oxidative stress. FASEB J. 17: 50-52 (2003)
  50. Mizuno M et al. Phosphatidylinositol 3-kinase: a molecule mediating BDNF-dependent spatial memory formation. Mol. Psychiatry 8: 217-224 (2003)
  51. Tran MH et al. Tyrosine nitration of a synaptic protein synaptophysin contributes to amyloid β-peptide-induced cholinergic dysfunction. Mol. Psychiatry 8: 407-412 (2003)
  52. Miyamoto Y et al. Lower sensitivity to stress and altered monoaminergic neuronal function in mice lacking the NMDA receptor e4 subunit. J. Neurosci. 22: 2335-2342 (2002)
  53. Tran MH et al. Amyloid β-peptide induces nitric oxide production in rat hippocampus: association with cholinergic dysfunction and amelioration by inducible nitric oxide synthase inhibitors. FASEB J. 15: 1407-1409 (2001)
  54. Miyamato Y et al. Hyperfunction of dopaminergic and serotonergic neuronal systems in mice lacking NMDA receptor e1 subunit. J. Neurosci. 21: 750-757 (2001)
  55. Mizuno M et al. Involvement of BDNF in spatial memory formation and maintenance in a radial arm maze test in rats. J. Neurosci. 20: 7116-7121


Research Award from the Japanese Pharmacological Society (1997)
The Pharmaceutical Society of Japan Award for Divisional Scientific Promotions (2008)