Updated on 2024/10/09

写真a

 
SHIMOHATA Atsushi
 
Organization
Research Institute of Environmental Medicine Division of Stress Recognition and Response Designated assistant professor
Title
Designated assistant professor
External link

Degree 1

  1. 博士（学術） （ 2017.9   埼玉大学 ） 

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Research Interests 9

  1. behavioral analysis

  2. mGluR6

  3. monoamine

  4. Model mouse

  5. Microglia

  6. Dopamine

  7. Down Syndrome

  8. Alzhimer's disease

  9. GPCR

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Research Areas 6

  1. Life Science / Cognitive and brain science

  2. Life Science / Psychiatry

  3. Life Science / Neuroscience-general

  4. Life Science / Function of nervous system

  5. Life Science / Pathophysiologic neuroscience

  6. Life Science / Molecular biology

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Research History 5

  1. 名古屋大学環境医学研究所   病態神経科学分野   特任助教

    2023.4

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  2. Nippon Medical School

    2018.4 - 2023.3

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  3. 理化学研究所   神経遺伝研究チーム   研究員

    2017.10 - 2018.3

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  4. 理化学研究所   神経遺伝研究チーム   リサーチアソシエイト

    2011.10 - 2017.9

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  5. 理化学研究所   神経遺伝研究チーム   テクニカルスタッフ

    2001.4 - 2011.9

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Education 2

  1. Saitama University   Graduate School of Science and Engineering

    2011.10 - 2017.9

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  2. University of Tsukuba

    1999.4 - 2001.3

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Professional Memberships 1

  1. 日本神経科学学会

    2020.2

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Papers 19

  1. The intracellular C-terminal domain of mGluR6 contains ER retention motifs. Reviewed International journal

    Atsushi Shimohata, Dilip Rai, Takumi Akagi, Sumiko Usui, Ikuo Ogiwara, Makoto Kaneda

    Molecular and cellular neurosciences   Vol. 126   page： 103875 - 103875   2023.9

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    Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

    Metabotropic glutamate receptor 6 (mGluR6) predominantly localizes to the postsynaptic sites of retinal ON-bipolar cells, at which it recognizes glutamate released from photoreceptors. The C-terminal domain (CTD) of mGluR6 contains a cluster of basic amino acids resembling motifs for endoplasmic reticulum (ER) retention. We herein investigated whether these basic residues are involved in regulating the subcellular localization of mGluR6 in 293 T cells expressing mGluR6 CTD mutants using immunocytochemistry, immunoprecipitation, and flow cytometry. We showed that full-length mGluR6 localized to the ER and cell surface, whereas mGluR6 mutants with 15- and 20-amino acid deletions from the C terminus localized to the ER, but were deficient at the cell surface. We also demonstrated that the cell surface deficiency of mGluR6 mutants was rescued by introducing an alanine substitution at basic residues within the CTD. The surface-deficient mGluR6 mutant still did not localize to the cell surface and was retained in the ER when co-expressed with surface-expressible constructs, including full-length mGluR6, even though surface-deficient and surface-expressible constructs formed heteromeric complexes. The co-expression of the surface-deficient mGluR6 mutant reduced the surface levels of surface-expressible constructs. These results indicate that basic residues in the mGluR6 CTD served as ER retention signals. We suggest that exposed ER retention motifs in the aberrant assembly containing truncated or misfolded mGluR6 prevent these protein complexes from being transported to the cell surface.

    DOI： 10.1016/j.mcn.2023.103875

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  2. CUX2 deficiency causes facilitation of excitatory synaptic transmission onto hippocampus and increased seizure susceptibility to kainate Reviewed

    Suzuki Toshimitsu, Tatsukawa Tetsuya, Sudo Genki, Delandre Caroline, Pai Yun Jin, Miyamoto Hiroyuki, Raveau Matthieu, Shimohata Atsushi, Ohmori Iori, Hamano Shin-ichiro, Haginoya Kazuhiro, Uematsu Mitsugu, Takahashi Yukitoshi, Morimoto Masafumi, Fujimoto Shinji, Osaka Hitoshi, Oguni Hirokazu, Osawa Makiko, Ishii Atsushi, Hirose Shinichi, Kaneko Sunao, Inoue Yushi, Moore Adrian Walton, Yamakawa Kazuhiro

    SCIENTIFIC REPORTS   Vol. 12 ( 1 ) page： 6505   2022.5

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    Authorship：Lead author   Language：English   Publisher：Scientific Reports  

    CUX2 gene encodes a transcription factor that controls neuronal proliferation, dendrite branching and synapse formation, locating at the epilepsy-associated chromosomal region 12q24 that we previously identified by a genome-wide association study (GWAS) in Japanese population. A CUX2 recurrent de novo variant p.E590K has been described in patients with rare epileptic encephalopathies and the gene is a candidate for the locus, however the mutation may not be enough to generate the genome-wide significance in the GWAS and whether CUX2 variants appear in other types of epilepsies and physiopathological mechanisms are remained to be investigated. Here in this study, we conducted targeted sequencings of CUX2, a paralog CUX1 and its short isoform CASP harboring a unique C-terminus on 271 Japanese patients with a variety of epilepsies, and found that multiple CUX2 missense variants, other than the p.E590K, and some CASP variants including a deletion, predominantly appeared in patients with temporal lobe epilepsy (TLE). The CUX2 variants showed abnormal localization in human cell culture analysis. While wild-type CUX2 enhances dendritic arborization in fly neurons, the effect was compromised by some of the variants. Cux2- and Casp-specific knockout mice both showed high susceptibility to kainate, increased excitatory cell number in the entorhinal cortex, and significant enhancement in glutamatergic synaptic transmission to the hippocampus. CASP and CUX2 proteins physiologically bound to each other and co-expressed in excitatory neurons in brain regions including the entorhinal cortex. These results suggest that CUX2 and CASP variants contribute to the TLE pathology through a facilitation of excitatory synaptic transmission from entorhinal cortex to hippocampus.

    DOI： 10.1038/s41598-022-10715-w

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  3. CUX2 mutations in temporal lobe epilepsy; increased kainate susceptibility and excitatory input to hippocampus in deficient mice Reviewed

    Toshimitsu Suzuki, Tetsuya Tatsukawa, Genki Sudo, Caroline Delandre, Yun Jin Pai, Hiroyuki Miyamoto, Matthieu Raveau, Atsushi Shimohata, Iori Ohmori, Shin-ichiro Hamano, Kazuhiro Haginoya, Mitsugu Uematsu, Yukitoshi Takahashi, Masafumi Morimoto, Shinji Fujimoto, Hitoshi Osaka, Hirokazu Oguni, Makiko Osawa, Atsushi Ishii, Shinichi Hirose, Sunao Kaneko, Yushi Inoue, Adrian Walton Moore, Kazuhiro Yamakawa

    bioRxiv     2021.9

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    Language：English   Publisher：Cold Spring Harbor Laboratory  

    <title>Abstract</title><italic>CUX2</italic> gene encodes a transcription factor that controls neuronal proliferation, dendrite branching and synapse formation, locating at the epilepsy-associated chromosomal region 12q24 that we previously identified by a genome-wide association study (GWAS) in Japanese population. A <italic>CUX2</italic> recurrent <italic>de novo</italic> variant p.E590K has been described in patients with rare epileptic encephalopathies and the gene is a candidate for the locus, however the mutation may not be enough to generate the genome-wide significance in the GWAS and whether <italic>CUX2</italic> variants appear in other types of epilepsies and physiopathological mechanisms are remained to be investigated. Here in this study, we conducted targeted sequencings of <italic>CUX2</italic>, a paralog <italic>CUX1</italic> and its short isoform <italic>CASP</italic> harboring a unique C-terminus on 271 Japanese patients with a variety of epilepsies, and found that multiple <italic>CUX2</italic> missense variants, other than the p.E590K, and some <italic>CASP</italic> variants including a deletion, predominantly appeared in patients with temporal lobe epilepsy (TLE). Human cell culture and fly dendritic arborization analyses revealed loss-of- function properties for the <italic>CUX2</italic> variants. <italic>Cux2</italic>- and <italic>Casp</italic>-specific knockout mice both showed high susceptibility to kainate, increased excitatory cell number in the entorhinal cortex, and significant enhancement in glutamatergic synaptic transmission to the hippocampus. CASP and CUX2 proteins physiologically bound to each other and co-expressed in excitatory neurons in brain regions including the entorhinal cortex. These results suggest that <italic>CUX2</italic> and <italic>CASP</italic> variants contribute to the TLE pathology through a facilitation of excitatory synaptic transmission from entorhinal cortex to hippocampus.

    DOI： 10.1101/2021.09.17.460803

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  4. Involvement of the C‐terminal domain in cell surface localization and G‐protein coupling of mGluR6 Reviewed

    Dilip Rai, Takumi Akagi, Atsushi Shimohata, Toshiyuki Ishii, Mie Gangi, Takuma Maruyama, Yuko Wada‐Kiyama, Ikuo Ogiwara, Makoto Kaneda

    Journal of Neurochemistry   Vol. 158 ( 4 ) page： 837 - 848   2021.8

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    Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

    DOI： 10.1111/jnc.15217

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    Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1111/jnc.15217

  5. The C‐terminal domain is required for mGluR6 cell‐surface localization Reviewed

    Atsushi Shimohata, Dilip Rai, Takumi Akagi, Toshiyuki Ishii, Mie Gangi, Takuma Maruyama, Yuko Wada‐Kiyama, Ikuo Ogiwara, Makoto Kaneda

    The FASEB Journal   Vol. 35 ( S1 )   2021.5

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    Authorship：Lead author   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

    DOI： 10.1096/fasebj.2021.35.s1.01591

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  6. Impairment of spatial memory accuracy improved by Cbr1 copy number resumption and GABAB receptor-dependent enhancement of synaptic inhibition in Down syndrome model mice Reviewed

    Fumiko Arima-Yoshida, Matthieu Raveau, Atsushi Shimohata, Kenji Amano, Akihiro Fukushima, Masashi Watanave, Shizuka Kobayashi, Satoko Hattori, Masaya Usui, Haruhiko Sago, Nobuko Mataga, Tsuyoshi Miyakawa, Kazuhiro Yamakawa, Toshiya Manabe

    Scientific Reports   Vol. 10 ( 1 )   2020.12

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    Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

    DOI： 10.1038/s41598-020-71085-9

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    Other Link： http://www.nature.com/articles/s41598-020-71085-9

  7. A recurrent PJA1 variant in trigonocephaly and neurodevelopmental disorders Reviewed

    Toshimitsu Suzuki, Toshifumi Suzuki, Matthieu Raveau, Noriko Miyake, Genki Sudo, Yoshinori Tsurusaki, Takaki Watanabe, Yuki Sugaya, Tetsuya Tatsukawa, Emi Mazaki, Atsushi Shimohata, Itaru Kushima, Branko Aleksic, Tomoko Shiino, Tomoko Toyota, Yoshimi Iwayama, Kentaro Nakaoka, Iori Ohmori, Aya Sasaki, Ken Watanabe, Shinichi Hirose, Sunao Kaneko, Yushi Inoue, Takeo Yoshikawa, Norio Ozaki, Masanobu Kano, Takeyoshi Shimoji, Naomichi Matsumoto, Kazuhiro Yamakawa

    Annals of Clinical and Translational Neurology   Vol. 7 ( 7 ) page： 1117 - 1131   2020.7

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    Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

    DOI： 10.1002/acn3.51093

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    Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1002/acn3.51093

  8. Perturbation of the immune cells and prenatal neurogenesis by the triplication of the Erg gene in mouse models of Down syndrome Reviewed

    Keiichi Ishihara, Ryohei Shimizu, Kazuyuki Takata, Eri Kawashita, Kenji Amano, Atsushi Shimohata, Donovan Low, Takeshi Nabe, Haruhiko Sago, Warren S. Alexander, Florent Ginhoux, Kazuhiro Yamakawa, Satoshi Akiba

    Brain Pathology   Vol. 30 ( 1 ) page： 75 - 91   2020.1

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    DOI： 10.1111/bpa.12758

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    Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1111/bpa.12758

  9. Impaired cortico-striatal excitatory transmission triggers epilepsy Reviewed

    Hiroyuki Miyamoto, Tetsuya Tatsukawa, Atsushi Shimohata, Tetsushi Yamagata, Toshimitsu Suzuki, Kenji Amano, Emi Mazaki, Matthieu Raveau, Ikuo Ogiwara, Atsuko Oba-Asaka, Takao K. Hensch, Shigeyoshi Itohara, Kenji Sakimura, Kenta Kobayashi, Kazuto Kobayashi, Kazuhiro Yamakawa

    Nature Communications   Vol. 10 ( 1 ) page： 1917   2019.4

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    Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

    DOI： 10.1038/s41467-019-09954-9

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    Other Link： http://www.nature.com/articles/s41467-019-09954-9

  10. Impairments in social novelty recognition and spatial memory in mice with conditional deletion of Scn1a in parvalbumin-expressing cells Reviewed

    Tetsuya Tatsukawa, Ikuo Ogiwara, Emi Mazaki, Atsushi Shimohata, Kazuhiro Yamakawa

    Neurobiology of Disease   Vol. 112   page： 24 - 34   2018.4

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    Language：English   Publishing type：Research paper (scientific journal)   Publisher：Academic Press Inc.  

    Loss of function mutations in the SCN1A gene, which encodes the voltage-gated sodium channel Nav1.1, have been described in the majority of Dravet syndrome patients presenting with epileptic seizures, hyperactivity, autistic traits, and cognitive decline. We previously reported predominant Nav1.1 expression in parvalbumin-expressing (PV+) inhibitory neurons in juvenile mouse brain and observed epileptic seizures in mice with selective deletion of Scn1a in PV+ cells mediated by PV-Cre transgene expression (Scn1afl/+/PV-Cre-TG). Here we investigate the behavior of Scn1afl/+/PV-Cre-TG mice using a comprehensive battery of behavioral tests. We observed that Scn1afl/+/PV-Cre-TG mice display hyperactive behavior, impaired social novelty recognition, and altered spatial memory. We also generated Scn1afl/+/SST-Cre-KI mice with a selective Scn1a deletion in somatostatin-expressing (SST+) inhibitory neurons using an SST-IRES-Cre knock-in driver line. We observed that Scn1afl/+/SST-Cre-KI mice display no spontaneous convulsive seizures and that Scn1afl/+/SST-Cre-KI mice have a lowered threshold temperature for hyperthermia-induced seizures, although their threshold values are much higher than those of Scn1afl/+/PV-Cre-TG mice. We finally show that Scn1afl/+/SST-Cre-KI mice exhibited no noticeable behavioral abnormalities. These observations suggest that impaired Nav1.1 function in PV+ interneurons is critically involved in the pathogenesis of hyperactivity, autistic traits, and cognitive decline, as well as epileptic seizures, in Dravet syndrome.

    DOI： 10.1016/j.nbd.2018.01.009

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  11. DYRK1A-haploinsufficiency in mice causes autistic-like features and febrile seizures. Reviewed International journal

    Matthieu Raveau, Atsushi Shimohata, Kenji Amano, Hiroyuki Miyamoto, Kazuhiro Yamakawa

    Neurobiology of disease   Vol. 110   page： 180 - 191   2018.2

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    Mutations and copy number variants affecting DYRK1A gene encoding the dual-specificity tyrosine phosphorylation-regulated kinase 1A are among the most frequent genetic causes of neurodevelopmental disorders including autism spectrum disorder (ASD) associated with microcephaly, febrile seizures and severe speech acquisition delay. Here we developed a mouse model harboring a frame-shift mutation in Dyrk1a resulting in a protein truncation and elimination of its kinase activity site. Dyrk1a+/- mice showed significant impairments in cognition and cognitive flexibility, communicative ultrasonic vocalizations, and social contacts. Susceptibility to hyperthermia-induced seizures was also significantly increased in these mice. The truncation leading to haploinsufficiency of DYRK1A in mice thus recapitulates the syndromic phenotypes observed in human patients and constitutes a useful model for further investigations of the mechanisms leading to ASD, speech delay and febrile seizures.

    DOI： 10.1016/j.nbd.2017.12.003

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  12. Potentiation of excitatory synaptic transmission ameliorates aggression in mice with Stxbp1 haploinsufficiency Reviewed

    Hiroyuki Miyamoto, Atsushi Shimohata, Manabu Abe, Teruo Abe, Emi Mazaki, Kenji Amano, Toshimitsu Suzuki, Tetsuya Tatsukawa, Shigeyoshi Itohara, Kenji Sakimura, Kazuhiro Yamakawa

    HUMAN MOLECULAR GENETICS   Vol. 26 ( 24 ) page： 4961 - 4974   2017.12

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    Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS  

    Genetic studies point to a major role of de novo mutations in neurodevelopmental disorders of intellectual disability, autism spectrum disorders, and epileptic encephalopathy. The STXBP1 gene encodes the syntaxin-binding protein 1 (Munc18-1) that critically controls synaptic vesicle exocytosis and synaptic transmission. This gene harbors a high frequency of de novo mutations, which may play roles in these neurodevelopmental disorders. However, the system and behavioral-level pathophysiological changes caused by these genetic defects remain poorly understood. Constitutional (Stxbp1(+/-)), dorsal-telencephalic excitatory (Stxbp1(fl/+)/Emx), or global inhibitory neuron-specific (Stxbp1(fl/+)/Vgat) mice were subjected to a behavioral test battery examining locomotor activity, anxiety, fear learning, and social interactions including aggression. Furthermore, measurements of local field potentials in multiple regions of the brain were performed. Stxbp1(+/-) male mice exhibited enhanced aggressiveness and impaired fear learning associated with elevated gamma activity in several regions of the brain including the prefrontal cortex. Stxbp1(fl/+)/Emx mice showed fear-learning deficits, but neither Stxbp1(fl/+)/Emx nor Stxbp1(fl/+)/Vgat mice showed increased aggressiveness. Pharmacological potentiation of the excitatory transmission at active synapses via the systemic administration of ampakine CX516, which enhances the excitatory postsynaptic function, ameliorated the aggressive phenotype of Stxbp1(+/-) mice. These findings suggest that synaptic impairments of the dorsal telencephalic and subcortical excitatory neurons cause learning deficits and enhanced aggression in Stxbp1(+/-) mice, respectively. Additionally, normalizing the excitatory synaptic transmission is a potential therapeutic option for managing aggressiveness in patients with STXBP1 mutations.

    DOI： 10.1093/hmg/ddx379

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  13. Ts1Cje Down syndrome model mice exhibit environmental stimuli-triggered locomotor hyperactivity and sociability concurrent with increased flux through central dopamine and serotonin metabolism Reviewed

    Atsushi Shimohata, Keiichi Ishihara, Satoko Hattori, Hiroyuki Miyamoto, Hiromasa Morishita, Guy Ornthanalai, Matthieu Raveau, Abdul Shukkur Ebrahim, Kenji Amano, Kazuyuki Yamada, Haruhiko Sago, Satoshi Akiba, Nobuko Mataga, Niall P. Murphy, Tsuyoshi Miyakawa, Kazuhiro Yamakawa

    EXPERIMENTAL NEUROLOGY   Vol. 293   page： 1 - 12   2017.7

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    Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE  

    Ts1Cje mice have a segmental trisomy of chromosome 16 that is orthologous to human chromosome 21 and display Down syndrome-like cognitive impairments. Despite the occurrence of affective and emotional impairments in patients with Down syndrome, these parameters are poorly documented in Down syndrome mouse models, including Ts1Cje mice. Here, we conducted comprehensive behavioral analyses, including anxiety-, sociability-, and depression-related tasks, and biochemical analyses of monoamines and their metabolites in Ts1Cje mice. Ts1Cje mice showed enhanced locomotor activity in novel environments and increased social contact with unfamiliar partners when compared with wild-type littermates, but a significantly lower activity in familiar environments. Ts1Cje mice also exhibited some signs of decreased depression like-behavior. Furthermore, Ts1Cje mice showed monoamine abnormalities, including increased extracellular dopamine and serotonin, and enhanced catabolism in the striatum and ventral forebrain. This study constitutes the first report of deviated monoamine metabolism that may help explain the basis for abnormal behaviors, including the environmental stimuli-triggered hyperactivity, increased sociability and decreased depression-like behavior in Ts1Cje mice. (C) 2017 Elsevier Inc. All rights reserved.

    DOI： 10.1016/j.expneurol.2017.03.009

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  14. Brain ventriculomegaly in Down syndrome mice is caused by Pcp4 dose-dependent cilia dysfunction Reviewed

    Matthieu Raveau, Takashi Nakahari, Sachie Asada, Keiichi Ishihara, Kenji Amano, Atsushi Shimohata, Haruhiko Sago, Kazuhiro Yamakawa

    HUMAN MOLECULAR GENETICS   Vol. 26 ( 5 ) page： 923 - 931   2017.3

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    Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS  

    Down syndrome is a leading cause of congenital intellectual disability caused by an additional copy of the chromosome 21. Patients display physiological and morphological changes affecting the brain and its function. Previously we showed that Ts1Cje and Ts2Cje, Down syndrome mouse models carrying overlapping trisomic segments of different length, show similar ventriculomegaly and neurogenesis dysfunction leading to the hypothesis of a cause-consequence relationship between these phenotypes. However, we here discovered that Ts1Rhr Down syndrome model, carrying an even shorter trisomic segment, was sufficient to trigger ventricular enlargement and ependymal cilia beating deficiency without affecting neurogenesis. We further found that Pcp4 gene on the Ts1Rhr trisomic segment is expressed in ependymal cells, and its resumption to two copies rescued both ventricular enlargement and cilia dysfunction in Ts1Rhr mice. This work underlines a Pcp4-dependent ciliopathy in Down syndrome brain affecting cerebrospinal fluid flow.

    DOI： 10.1093/hmg/ddx007

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  15. Enlarged Brain Ventricles and Impaired Neurogenesis in the Ts1Cje and Ts2Cje Mouse Models of Down Syndrome Reviewed

    Keiichi Ishihara, Kenji Amano, Eiichi Takaki, Atsushi Shimohata, Haruhiko Sago, Charles J. Epstein, Kazuhiro Yamakawa

    CEREBRAL CORTEX   Vol. 20 ( 5 ) page： 1131 - 1143   2010.5

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    Down syndrome (DS) is the most common cause of mental retardation. Although structural and neurogenic abnormalities have been shown in the brains of DS patients, the molecular etiology is still unknown. To define it, we have performed structural and histological examinations of the brains of Ts1Cje and Ts2Cje, 2 mouse models for DS. These mice carry different length of trisomic segments of mouse chromosome 16 that are orthologous to human chromosome 21. At 3 months of age, ventricular enlargements were observed in both Ts1Cje and Ts2Cje brains at a similar degree. Both mice also showed decreases of the number of doublecortin-positive neuroblasts and thymidine-analog BrdU-labeled proliferating cells in the subventricular zone of the lateral ventricles (LVs) and in the hippocampal dentate gyrus at a similar degree, suggesting impaired adult neurogenesis. Additionally, at embryonic day 14.5, both strains of mice, when compared with diploid littermates, had smaller brains and decreased cortical neurogenesis that could possibly contribute to the ventricular enlargements observed in adulthood. Our findings suggest that the trisomic segment of the Ts1Cje mouse, which is shared with Ts2Cje, contains the genes that are responsible for these abnormal phenotypes and could be relevant to the mental retardation associated with DS.

    DOI： 10.1093/cercor/bhp176

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  16. Increased lipid peroxidation in Down's syndrome mouse models Reviewed

    Keiichi Ishihara, Kenji Amano, Eiichi Takaki, Abdul Shukkur Ebrahim, Atsushi Shimohata, Noriko Shibazaki, Ikuyo Inoue, Mayuko Takaki, Yuto Ueda, Haruhiko Sago, Charles J. Epstein, Kazuhiro Yamakawa

    JOURNAL OF NEUROCHEMISTRY   Vol. 110 ( 6 ) page： 1965 - 1976   2009.9

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    Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

    Elevated oxidative stress has been suggested to be associated with the features of Down's syndrome (DS). We previously reported increased oxidative stress in cultured cells from the embryonic brain of Ts1Cje, a mouse genetic DS model. However, since in vivo evidence for increased oxidative stress is lacking, we here examined lipid peroxidation, a typical marker of oxidative stress, in the brains of Ts1Cje and another DS mouse model Ts2Cje with an overlapping but larger trisomic segment. Accumulations of proteins modified with the lipid peroxidation-derived products, 13-hydroperoxy-9Z,11E-octadecadienoic acid and 4-hydroxy-2-nonenal were markedly increased in Ts1Cje and Ts2Cje brains. Analysis with oxidation-sensitive fluorescent probe also showed that reactive oxygen species themselves were increased in Ts1Cje brain. However, electron spin resonance analysis of microdialysate from the hippocampus of Ts1Cje showed that antioxidant activity remained unaffected, suggesting that the reactive oxygen species production was accelerated in Ts1Cje. Proteomics approaches with mass spectrometry identified the proteins modified with 13-hydroperoxy-9Z, 11E-octadecadienoic acid and/or 4-hydroxy-2-nonenal to be involved in either ATP generation, the neuronal cytoskeleton or antioxidant activity. Structural or functional impairments of these proteins by such modifications may contribute to the DS features such as cognitive impairment that are present in the Ts1Cje mouse.

    DOI： 10.1111/j.1471-4159.2009.06294.x

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  17. DSCAM Deficiency Causes Loss of Pre-Inspiratory Neuron Synchroneity and Perinatal Death Reviewed

    Kenji Amano, Morimitsu Fujii, Satoru Arata, Takuro Tojima, Masaharu Ogawa, Noriyuki Morita, Atsushi Shimohata, Teiichi Furuichi, Shigeyoshi Itohara, Hiroyuki Kamiguchi, Julie R. Korenberg, Akiko Arata, Kazuhiro Yamakawa

    JOURNAL OF NEUROSCIENCE   Vol. 29 ( 9 ) page： 2984 - 2996   2009.3

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    Language：English   Publishing type：Research paper (scientific journal)   Publisher：SOC NEUROSCIENCE  

    Down syndrome cell adhesion molecule (DSCAM) is a neural adhesion molecule that plays diverse roles in neural development. We disrupted the Dscam locus in mice and found that the null mutants (Dscam(-/-)) died within 24 h after birth. Whole-body plethysmography showed irregular respiration and lower ventilatory response to hypercapnia in the null mutants. Furthermore, a medulla-spinal cord preparation of Dscam(-/-) mice showed that the C4 ventral root activity, which drives diaphragm contraction for inspiration, had an irregular rhythm with frequent apneas. Optical imaging of the preparation using voltage-sensitive dye revealed that the pre-inspiratory neurons located in the rostral ventrolateral medulla and belonging to the rhythm generator for respiration, lost their synchroneity in Dscam(-/-) mice. Dscam(-/-) mice, which survived to adulthood without any overt abnormalities, also showed irregular respiration but milder than Dscam(-/-) mice. These results suggest that DSCAM plays a critical role in central respiratory regulation in a dosage-dependent manner.

    DOI： 10.1523/JNEUROSCI.3624-08.2009

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  18. Mitochondrial dysfunction and tau hyperphosphorylation in Ts1Cje, a mouse model for Down syndrome Reviewed

    Ebrahim Abdul Shukkur, Atsushi Shimohata, Takumi Akagi, Wenxin Yu, Mika Yamaguchi, Miyuki Murayama, Dehua Chui, Tamaki Takeuchi, Kenji Amano, Karthik Harve Subramhanya, Tsutomu Hashikawa, Haruhiko Sago, Charles J. Epstein, Akihiko Takashima, Kazuhiro Yamakawa

    HUMAN MOLECULAR GENETICS   Vol. 15 ( 18 ) page： 2752 - 2762   2006.9

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    Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS  

    Trisomy 21 or Down syndrome (DS) is the most common genetic birth defect associated with mental retardation. The over-expression of genes on chromosome 21, including SOD1 (Cu/Zn superoxide dismutase) and APP (amyloid-beta precursor protein) is believed to underlie the increased oxidative stress and neurodegeneration commonly described in DS. However, a segmental trisomy 16 mouse model for DS, Ts1Cje, has a subset of triplicated human chromosome 21 gene orthologs that exclude APP and SOD1. Here, we report that Ts1Cje brain shows decreases of mitochondrial membrane potential and ATP production, increases of reactive oxygen species, hyperphosphorylation of tau without NFT formation, increase of GSK3 beta and JNK/SAPK activities and unaltered A beta PP metabolism. Our findings suggest that genes on the trisomic Ts1Cje segment other than APP and SOD1 can cause oxidative stress, mitochondrial dysfunction and hyperphosphorylation of tau, all of which may play critical roles in the pathogenesis of mental retardation in DS.

    DOI： 10.1093/hmg/ddl211

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  19. Aβ42-positive non-pyramidal neurons around amyloid plaques in Alzheimer's disease Reviewed

    Akihide Mochizuki;Akira Tamaoka;Atsushi Shimohata;Yasuko Komatsuzaki;Shin'Ichi Shoji

      Vol. 355 ( 9197 ) page： 42 - 43   2000.1

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    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1016/S0140-6736(99)04937-5

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MISC 33

  1. アルツハイマー病モデルマウスにおけるオーファンGタンパク質共役受容体の遺伝子変動

    Neuro2024、第47回日本神経科学大会     2024.7

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    Authorship：Lead author  

  2. The intracellular C-terminal domain of mGluR6 contains ER retention motifs

    下畑充志 赤木巧 荻原郁夫 金田誠

        2023.8

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  3. 代謝型グルタミン酸6型受容体の細胞内C末端領域には小胞体保持配列が存在する

    下畑充志, 赤木巧, 荻原郁夫, 金田誠

    日本生理学会 第100回記念大会プログラム集     2023.3

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  4. 代謝型グルタミン酸6型受容体の細胞内輸送に関与するC末端特異的配列の探索

    下畑充志, 赤木巧, 荻原郁夫, 金田誠

    日本神経化学会大会抄録集(Web)   Vol. 65th   2022

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    J-GLOBAL

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  5. 代謝型グルタミン酸6型受容体C末端領域と相互作用するタンパク質の探索

    下畑充志, 赤木巧, 荻原郁夫, 金田誠

    日本神経科学学会     2020.7

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  6. 代謝型グルタミン酸6型受容体の細胞膜発現におけるC末端領域の役割

    下畑充志, Rai Dilip, 赤木巧, 石井俊行, 雁木美衣, 丸山拓真, 木山裕子, 荻原郁夫, 金田誠

    日本生理学会 第99回大会プログラム集     2020.3

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  7. ダウン症モデルマウス(Ts1Cje)に見られた活動量増加と脳内モノアミン量の上昇

    下畑充志, 石原慶一, 宮本浩行, 尾見裕子, 服部聡子, 森下泰全, 俣賀宣子, 左合治彦, 宮川剛, 山川和弘

    日本人類遺伝学会大会プログラム・抄録集   Vol. 60th   2015

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    J-GLOBAL

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  8. ダウン症モデルマウス(Ts1Cje)の異常におけるダウン症責任領域内遺伝子:Cbr1の評価

    下畑充志, 左合治彦, 山川和弘

    日本人類遺伝学会大会プログラム・抄録集   Vol. 58th   2013

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    J-GLOBAL

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  9. 微小核細胞融合技術を用いた新しいトリソミーマウスモデルの作製

    下畑充志, 天野賢治, 香月康宏, 押村光雄, 山川和弘

    日本人類遺伝学会大会プログラム・抄録集   Vol. 57th   2012

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    J-GLOBAL

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  10. ダウン症モデルマウス(Ts1Cje)におけるダウン症責任候補遺伝子Cbr1(Carbonyl reductase 1)の検討

    下畑 充志, 山川 和弘

    脳と発達   Vol. 41 ( Suppl. ) page： S408 - S408   2009.5

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    Authorship：Lead author   Language：Japanese   Publisher：(一社)日本小児神経学会  

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  11. ダウン症モデルマウス(Ts1Cje)に見られた行動抑制障害

    下畑 充志, 山川 和弘

    脳と発達   Vol. 40 ( Suppl. ) page： S407 - S407   2008.5

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    Authorship：Lead author   Language：Japanese   Publisher：(一社)日本小児神経学会  

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  12. Behavioral phenotyping of the Ts1Cje, a model for Down syndrome

    Atsushi Shimohata, Hiroko Omi, Ebrahim Abdul S, Kazuyuki Yamade, Epstein Charles J, Haruhiko Sago, Kazuhiro Yamakawa

    NEUROSCIENCE RESEARCH   Vol. 61   page： S136 - S136   2008

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    Authorship：Lead author   Language：English   Publishing type：Research paper, summary (international conference)   Publisher：ELSEVIER IRELAND LTD  

    Web of Science

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  13. ダウン症モデルマウス(TslCje)の行動異常とダウン症責任遺伝子の1つであるCbr1との関係について

    下畑充志, 左合治彦, 山川和弘

    日本人類遺伝学会大会プログラム・抄録集   Vol. 53rd   2008

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    J-GLOBAL

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  14. ダウン症モデルマウス(Ts1Cje)の行動学的異常に及ぼすエピガロカテキンガレート(EGCG)の影響

    下畑 充志, Ebrahim A. Shukkur, 山川 和弘

    脳と発達   Vol. 39 ( Suppl. ) page： S339 - S339   2007.6

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    Authorship：Lead author   Language：Japanese   Publisher：(一社)日本小児神経学会  

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  15. ダウン症モデルマウス(Ts1Cje)に見られた活動亢進と行動抑制障害

    下畑充志, 尾見裕子, EBRAHIM A Shukkur, 山田一之, 左合治彦, 山川和弘

    日本人類遺伝学会大会プログラム・抄録集   Vol. 52nd   2007

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    J-GLOBAL

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  16. Increased oxidative stress and mitochondrial dysfunction in Ts1Cje, a Down syndrome mouse model

    Atsushi Shimohata, A. S. Ebrahim, M. Yamaguchi, W. Yu, H. Sago, C. J. Epstein, K. Yamakawa

    NEUROSCIENCE RESEARCH   Vol. 55   page： S256 - S256   2006

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  17. ダウン症モデルマウス(Ts1Cje)の解析

    下畑 充志, 山川 和弘

    脳と発達   Vol. 37 ( Suppl. ) page： S292 - S292   2005.5

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    Authorship：Lead author   Language：Japanese   Publisher：(一社)日本小児神経学会  

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  18. ダウン症モデルマウスにおけるミトコンドリア機能異常の解析(Mitochondrial dysfunction in brain of the Down syndrome mouse model: Ts1 Cje)

    下畑 充志, Ebrahim A.S., 山田 一之, 天野 賢治, 赤木 巧, 竹内 環, 左合 治彦, Epstein C.J., 端川 勉, 山川 和弘

    神経化学   Vol. 43 ( 2-3 ) page： 502 - 502   2004.8

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    Authorship：Lead author   Language：English   Publisher：(一社)日本神経化学会  

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  19. ダウン症モデルマウスにおけるミトコンドリア機能異常の解析

    下畑 充志, 山川 和弘

    脳と発達   Vol. 35 ( Suppl. ) page： S310 - S310   2003.5

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    Authorship：Lead author   Language：Japanese   Publisher：(一社)日本小児神経学会  

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  20. アルツハイマー病モデルマウスにおけるオーファンGタンパク質共役受容体の遺伝子変動

    Neuro2024、第47回日本神経科学大会     2024.7

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  21. 電位依存性ナトリウムチャネルNav1.1と線維芽細胞増殖因子相同因子の相互作用

    荻原郁夫, 尹成珠, 下畑充志, 雁木美衣, 金田誠

    日本神経化学会大会抄録集(Web)   Vol. 65th   2022

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  22. 代謝型グルタミン酸受容体6型の細胞膜表面局在に関するN型糖鎖修飾の役割

    赤木巧, 下畑充志, 荻原郁夫, 金田誠

    日本神経化学会大会抄録集(Web)   Vol. 65th   2022

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  23. マウス網膜におけるP2X3受容体はON型およびOFF型網膜神経節細胞に対し非対称な応答を誘導する

    石井俊行, 下畑充志, 鈴木千晶, 下郡智美, 金田誠

    日本神経化学会大会抄録集(Web)   Vol. 65th   2022

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  24. DNAマイクロアレイ解析を用いたダウン症モデルマウスにおける脳発達遅滞の関連遺伝子の探索

    清水涼平, 杉本早希, 都志見文子, 脇木咲紀, 河下映里, 下畑充志, ALEXANDER Warren, 左合治彦, 山川和弘, 秋葉聡, 石原慶一

    日本薬学会年会要旨集(CD-ROM)   Vol. 138th   2018

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  25. ダウン症マウス脳での炎症関連遺伝子の発現亢進とその責任遺伝子の同定

    石原慶一, 天野賢治, 河下映里, 下畑充志, アレキサンダー ウォレン, 左合治彦, 山川和弘, 秋葉聡

    日本人類遺伝学会大会プログラム・抄録集   Vol. 62nd   2017

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  26. ダウン症マウスモデルを用いた神経新生の異常,酸化ストレスの亢進,脳質拡大に関与する染色体領域の解析

    天野賢治, 浅田幸江, RAVEAU Matthieu, 下畑充志, 左合治彦, 山川和弘

    日本人類遺伝学会大会プログラム・抄録集   Vol. 58th   2013

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  27. ダウン症マウスモデルの脳における神経伝達物質量の異常と代謝異常

    石原慶一, 石原慶一, ORNTHANALAI G. Veravej, 下畑充志, 天野賢治, 秋葉聡, 左合治彦, MURPHY P. Niall, 山川和弘

    日本薬学会年会要旨集   Vol. 130th ( 3 )   2010

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  28. GENETIC BACKGROUNDS AFFECT PERINATAL DEATH CAUSED BY DSCAM DEFICIENCY

    Kenji Amano, Morimitsu Fujii, Satoru Arata, Takuro Tojima, Masaharu Ogawa, Noriyuki Morita, Atsushi Shimohata, Teiichi Furuichi, Shigeyoshi Itohara, Hiroyuki Kamiguchi, Julie R. Korenberg, Akiko Arata, Kazuhiro Yamakawa

    JOURNAL OF PHYSIOLOGICAL SCIENCES   Vol. 59   page： 471 - 471   2009

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  29. ダウン症モデルマウスの脳室拡大およびニューロン新生異常

    石原慶一, 石原慶一, 天野賢治, 高木栄一, 下畑充志, 左合治彦, 山川和弘

    生化学     2009

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  30. Abnormality of central respiratory network in Dscam knock-out mouse

    Morimitsu Fujii, Kenji Amano, Satoru Arata, Atsushi Shimohata, Kazuhiro Yamakawa, Akiko Arata

    NEUROSCIENCE RESEARCH   Vol. 55   page： S89 - S89   2006

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  31. Tau hyperphosphorylation in Ts1Cje, a partial trisomy 16 mouse model for Down syndrome

    Ebralum Abdul, A. Shimohata, W. Yu, M. Yamaguchi, M. Murayama, D. Chui, T. Akagi, T. Takeuchi, K. Amano, H. S. Karthik, T. Hashikawa, H. Sago, C. J. Epstein, A. Takaswma, K. Yamakawa

    NEUROSCIENCE RESEARCH   Vol. 55   page： S256 - S256   2006

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  32. Homophilic binding of Dscam accelerates neurite extension

    Kenji Amano, Takuro Tojima, Masaharu Ogawa, Atsushi Shimohata, Shigeyoshi Itohara, Hiroyuki Kamiguchi, Kazuhiro Yamakawa

    NEUROSCIENCE RESEARCH   Vol. 55   page： S89 - S89   2006

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  33. アルツハイマー病における神経細胞内アミロイドβ蛋白(Aβ)と神経細胞死について

    望月昭英, 下畑充志, 玉岡晃, 庄司進一

    臨床神経学   Vol. 41 ( 11 )   2001

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Presentations 2

  1. The C-terminal domain is required for mGluR6 cell-surface localization.

    Atsushi Shimohata, Dilip Rai, Takumi Akagi, Atsushi Shimohata, Toshiyuki Ishii, Mie Gangi, Takuma Maruyama, Yuko Wada-Kiyama, Ikuo Ogiwara, Makoto Kaneda

    Expetimental Biology 2021 (EB 2021)  2021.4.27 

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    Event date： 2021.4

    Language：English   Presentation type：Poster presentation  

    File： Experimental Biology2021_postor.pdf

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  2. Analyses of partial trisomy 16 (Ts1Cje) mouse: a model for Down syndrome

    Atsushi Shimohata, Kazuhiro Yamakawa

    2006 

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KAKENHI (Grants-in-Aid for Scientific Research) 3

  1. アルツハイマー病におけるGPCRに着目したミクログリアの恒常性機能維持に関する研究

    Grant number：24K18618  2024.4 - 2027.3

    科学研究費助成事業  若手研究

    下畑 充志

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    Authorship：Principal investigator 

    Grant amount：\4680000 （ Direct Cost: \3600000 、 Indirect Cost：\1080000 ）

    アルツハイマー病(AD)は初老期に発症し認知機能が進行性に損なわれる難病である。脳内に異常タンパク質の沈着と神経炎症と呼ばれるグリア細胞の活性化が見られ脳内免疫細胞であるミクログリアと病態進行との関連が注目されている。我々の研究室では大規模なRNA-seq解析を行いミクログリアの恒常性遺伝子の低下が神経変性の程度とよく相関しており病態進行解明の鍵となることを見出した。本課題では我々が見つけた変動遺伝子に着目し、作動薬を用いてミクログリア恒常性機能の維持を誘導してこの機構を明らかにする。神経変性疾患における恒常性ミクログリアの神経保護機能を解明し新しいAD治療薬開発に結びつく研究を行う。

  2. Evaluation between Cbr1 copy number resumpsion and several abnormalities in Ts1Cje; a model for Down syndrome

    Grant number：24791097  2012.4 - 2014.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (B)  Grant-in-Aid for Young Scientists (B)

    SHIMOHATA Atsushi

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    Authorship：Principal investigator  Grant type：Competitive

    Grant amount：\4160000 （ Direct Cost: \3200000 、 Indirect Cost：\960000 ）

    The present study was designed to evaluate whether the copy number resumption of Cbr1 gene located on DS critical region might rescue phenotypes seen in Ts1Cje:a model mouse for DS. We prepared and analyzed the Ts1Cje/Cbr1(+/+/-) mice in which Cbr1 gene only is set back to a normal expression level. We found that Cbr1 gene was not directly involved in neither decreasing of Body weight, hyper activity and ventricular enlargement in Ts1Cje. However, its possible implication in learning and memory deficit or oxidative stress increase in Ts1Cje remains elusive. We should continue our assessment of gene copy number resumption and their potential rescue of Ts1Cje abnormalities.

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  3. Investigation of molecular pathology of Down syndrome by high efficient system

    Grant number：22390078  2010 - 2012

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)  Grant-in-Aid for Scientific Research (B)

    YAMAKAWA Kazuhiro

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    To understand the molecular pathology of Down syndrome, we established a high efficient system in that mouse models with partial trisomy 16 which is syntenic to human chromosome 21. We successfully established 1) Avian cells harboring partial mouse chromosome 16 segments, 2) Mouse ES cells harboring extra partial mouse chromosome 16 derived from the avian cells, and 3) Mice from those ES cells. These resources should greatly contribute to Down syndrome studies.

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Teaching Experience (Off-campus) 1

  1. 生理学実習

    （Nippon Medical School）

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