Updated on 2020/09/07




Degree Earned 【 display / non-display

  • The University of Tokyo -  Ph.D

Employment Record in Research 【 display / non-display

  • 2020.04

    Tokyo University of AgricultureFaculty of Life Sciences   Department of Bioscience   Professor  

Research Areas 【 display / non-display

  • Molecular biology

  • Brain biometrics

Published Papers 【 display / non-display

  • Pathogenic POGZ mutation causes impaired cortical development and reversible autism-like phenotypes.

    Kensuke Matsumura, Kaoru Seiriki, Shota Okada, Masashi Nagase, Shinya Ayabe, Ikuko Yamada, Tamio Furuse, Hirotoshi Shibuya, Yuka Yasuda, Hidenaga Yamamori, Michiko Fujimoto, Kazuki Nagayasu, Kana Yamamoto, Kohei Kitagawa, Hiroki Miura, Nanaka Gotoda-Nishimura, Hisato Igarashi, Misuzu Hayashida, Masayuki Baba, Momoka Kondo, Shigeru Hasebe, Kosei Ueshima, Atsushi Kasai, Yukio Ago, Atsuko Hayata-Takano, Norihito Shintani, Tokuichi Iguchi, Makoto Sato, Shun Yamaguchi, Masaru Tamura, Shigeharu Wakana, Atsushi Yoshiki, Ayako M Watabe, Hideyuki Okano, Kazuhiro Takuma, Ryota Hashimoto, Hitoshi Hashimoto, Takanobu Nakazawa

    Nature communications   11 ( 1 ) 859 - 859   2020.02  [Refereed]

    Academic JournalResearch paper (scientific journal)   Joint Work

    Pogo transposable element derived with ZNF domain (POGZ) has been identified as one of the most recurrently de novo mutated genes in patients with neurodevelopmental disorders (NDDs), including autism spectrum disorder (ASD), intellectual disability and White-Sutton syndrome; however, the neurobiological basis behind these disorders remains unknown. Here, we show that POGZ regulates neuronal development and that ASD-related de novo mutations impair neuronal development in the developing mouse brain and induced pluripotent cell lines from an ASD patient. We also develop the first mouse model heterozygous for a de novo POGZ mutation identified in a patient with ASD, and we identify ASD-like abnormalities in the mice. Importantly, social deficits can be treated by compensatory inhibition of elevated cell excitability in the mice. Our results provide insight into how de novo mutations on high-confidence ASD genes lead to impaired mature cortical network function, which underlies the cellular pathogenesis of NDDs, including ASD.

    DOI PubMed

  • (S)-norketamine and (2S,6S)-hydroxynorketamine exert potent antidepressant-like effects in a chronic corticosterone-induced mouse model of depression.

    Rei Yokoyama, Momoko Higuchi, Wataru Tanabe, Shinji Tsukada, Megumi Naito, Takumi Yamaguchi, Lu Chen, Atsushi Kasai, Kaoru Seiriki, Takanobu Nakazawa, Shinsaku Nakagawa, Kenji Hashimoto, Hitoshi Hashimoto, Yukio Ago

    Pharmacology, biochemistry, and behavior   191   172876 - 172876   2020.02  [Refereed]

    Academic JournalResearch paper (scientific journal)   Joint Work

    Clinical and preclinical studies have shown that the N-methyl-d-aspartate receptor antagonist ketamine exerts rapid and long-lasting antidepressant effects. Although ketamine metabolites might also have potential antidepressant properties, controversial results have been reported for (2R,6R)-hydroxynorketamine ((2R,6R)-HNK) in particular, and there is little information regarding the effects of other ketamine metabolites. Here we aimed to compare the effects of (R)-norketamine ((R)-NK), (S)-NK, (2R,6R)-HNK, and (2S,6S)-HNK in a mouse model of depression induced by chronic corticosterone (CORT) injection. None of the ketamine metabolites at doses up to 20 mg/kg showed antidepressant-like activity in naïve male C57BL6/J mice. Chronic CORT treatment increased immobility in the forced swim test and caused anhedonic-like behaviors in the female encounter test. A single administration of (S)-NK and (2S,6S)-HNK dose-dependently reduced the enhanced immobility at 30 min after injection in chronic CORT-treated mice, while (R)-NK or (2R,6R)-HNK did not. Additionally, (S)-NK and (2S,6S)-HNK, but not (R)-NK or (2R,6R)-HNK, improved chronic CORT-induced anhedonia at 24 h after the injection. These results suggest that (S)-ketamine metabolites (S)-NK and (2S,6S)-HNK have potent acute and sustained antidepressant effects in rodents.

    DOI PubMed

  • Autism-associated protein kinase D2 regulates embryonic cortical neuron development.

    Kensuke Matsumura, Masayuki Baba, Kazuki Nagayasu, Kana Yamamoto, Momoka Kondo, Kohei Kitagawa, Tomoya Takemoto, Kaoru Seiriki, Atsushi Kasai, Yukio Ago, Atsuko Hayata-Takano, Norihito Shintani, Toshihiko Kuriu, Tokuichi Iguchi, Makoto Sato, Kazuhiro Takuma, Ryota Hashimoto, Hitoshi Hashimoto, Takanobu Nakazawa

    Biochemical and biophysical research communications   519 ( 3 ) 626 - 632   2019.11  [Refereed]

    Academic JournalResearch paper (scientific journal)   Joint Work

    Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder, characterized by impaired social interaction, repetitive behavior and restricted interests. Although the molecular etiology of ASD remains largely unknown, recent studies have suggested that de novo mutations are significantly involved in the risk of ASD. We and others recently identified spontaneous de novo mutations in PKD2, a protein kinase D family member, in sporadic ASD cases. However, the biological significance of the de novo PKD2 mutations and the role of PKD2 in brain development remain unclear. Here, we performed functional analysis of PKD2 in cortical neuron development using in utero electroporation. PKD2 is highly expressed in cortical neural stem cells in the developing cortex and regulates cortical neuron development, including the neuronal differentiation of neural stem cells and migration of newborn neurons. Importantly, we determined that the ASD-associated de novo mutations impair the kinase activity of PKD2, suggesting that the de novo PKD2 mutations can be a risk factor for the disease by loss of function of PKD2. Our current findings provide novel insight into the molecular and cellular pathogenesis of ASD.

    DOI PubMed

  • Psychiatric-disorder-related behavioral phenotypes and cortical hyperactivity in a mouse model of 3q29 deletion syndrome.

    Masayuki Baba, Kazumasa Yokoyama, Kaoru Seiriki, Yuichiro Naka, Kensuke Matsumura, Momoka Kondo, Kana Yamamoto, Misuzu Hayashida, Atsushi Kasai, Yukio Ago, Kazuki Nagayasu, Atsuko Hayata-Takano, Akinori Takahashi, Shun Yamaguchi, Daisuke Mori, Norio Ozaki, Tadashi Yamamoto, Kazuhiro Takuma, Ryota Hashimoto, Hitoshi Hashimoto, Takanobu Nakazawa

    Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology   44 ( 12 ) 2125 - 2135   2019.11  [Refereed]

    Academic JournalResearch paper (scientific journal)   Joint Work

    3q29 microdeletion, a rare recurrent copy number variant (CNV), greatly confers an increased risk of psychiatric disorders, such as schizophrenia and autism spectrum disorder (ASD), as well as intellectual disability. However, disease-relevant cellular phenotypes of 3q29 deletion syndrome remain to be identified. To reveal the molecular and cellular etiology of 3q29 deletion syndrome, we generated a mouse model of human 3q29 deletion syndrome by chromosome engineering, which achieved construct validity. 3q29 deletion (Df/+) mice showed reduced body weight and brain volume and, more importantly, impaired social interaction and prepulse inhibition. Importantly, the schizophrenia-related impaired prepulse inhibition was reversed by administration of antipsychotics. These findings are reminiscent of the growth defects and neuropsychiatric behavioral phenotypes in patients with 3q29 deletion syndrome and exemplify that the mouse model achieves some part of face validity and predictive validity. Unbiased whole-brain imaging revealed that neuronal hyperactivation after a behavioral task was strikingly exaggerated in a restricted region of the cortex of Df/+ mice. We further elucidated the cellular phenotypes of neuronal hyperactivation and the reduction of parvalbumin expression in the cortex of Df/+ mice. Thus, the 3q29 mouse model provides invaluable insight into the disease-causative molecular and cellular pathology of psychiatric disorders.

    DOI PubMed

  • Pituitary Adenylate Cyclase-Activating Polypeptide Modulates Dendritic Spine Maturation and Morphogenesis via MicroRNA-132 Upregulation.

    Atsuko Hayata-Takano, Toshihiko Kamo, Harui Kijima, Kaoru Seiriki, Katsuya Ogata, Yukio Ago, Takanobu Nakazawa, Yusuke Shintani, Kosuke Higashino, Kazuki Nagayasu, Norihito Shintani, Atsushi Kasai, James A Waschek, Hitoshi Hashimoto

    The Journal of neuroscience : the official journal of the Society for Neuroscience   39 ( 22 ) 4208 - 4220   2019.05  [Refereed]

    Academic JournalResearch paper (scientific journal)   Joint Work

    Alterations in pituitary adenylate cyclase-activating polypeptide (PACAP), a multifunctional neuropeptide, and its receptors have been identified as risk factors for certain psychiatric disorders, including schizophrenia. Increasing evidence from human genetic and animal model studies suggest an association between various psychiatric disorders and altered dendritic spine morphology. In the present study, we investigated the role of exogenous and endogenous PACAP in spine formation and maturation. PACAP modified the density and morphology of PSD-95-positive spines in primary cultured hippocampal neurons. Notably, PACAP increased the levels of microRNA (miR)-132 and decreased expression of corresponding miR-132 target genes and protein expression of p250GAP, a miR-132 effector known to be involved in spine morphology regulation. In corroboration, PSD-95-positive spines were reduced in PACAP-deficient (PACAP-/-) mice versus WT mice. Golgi staining of hippocampal CA1 neurons revealed a reduced spine densities and atypical morphologies in the male PACAP-/- mice. Furthermore, viral miR-132 overexpression reversed the reduction in hippocampal spinal density in the male PACAP-/- mice. These results indicate that PACAP signaling plays a critical role in spine morphogenesis possibly via miR-132. We suggest that dysfunction of PACAP signaling may contribute to the pathogenesis of neuropsychiatric disorders, at least partly through its effects on spine formation.SIGNIFICANCE STATEMENT Pituitary adenylate cyclase-activating polypeptide (PACAP) signaling dysfunction and dendritic spine morphology alterations have recently been suggested as important pathophysiological mechanisms underlying several psychiatric and neurological disorders. In this study, we investigated whether PACAP regulates dendritic spine morphogenesis. In a combination of pharmacological and viral gain- and loss-of-function approaches in vitro and in vivo experiments, we found PACAP to increase the size and density of dendritic spines via miR-132 upregulation. Together, our data suggest that a dysfunction of PACAP signaling may contribute to the pathogenesis of neuropsychiatric disorders, at least partly through abnormal spine formation.

    DOI PubMed

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