Papers - HASHIMOTO Eri

Neuronal cell-type specific DNA methylation patterns of the Cacna1c gene.

Masaki Nishioka, Takafumi Shimada, Miki Bundo, Wataru Ukai, Eri Hashimoto, Toshikazu Saito, Yukiko Kano, Tsukasa Sasaki, Kiyoto Kasai, Tadafumi Kato, Kazuya Iwamoto

International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience   31 ( 2 ) 89 - 95  2013.04  [Refereed]  [International journal]

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Gene expression of the alpha-1 subunit of the L-type voltage-gated calcium channel, CACNA1C, is known to be complexly regulated. Because CACNA1C is not only a crucial gene in normal brain function but also a promising candidate risk gene for psychiatric disorders such as bipolar disorder and schizophrenia, elucidating the molecular basis of transcriptional regulatory mechanism will be critically important. Here we examined DNA methylation status of CpG islands and a CpG island shore on mouse Cacna1c in neuronal and non-neuronal nuclei, which were separated with a fluorescent activated cell sorting technique. We found that neurons and non-neurons showed differential DNA methylation profile on a CpG island shore. This difference was evolutionarily conserved in human neuronal and non-neuronal nuclei in the prefrontal cortex, suggesting that DNA methylation status on the CpG island shore of Cacna1c may have an important role in transcript regulation.

DOI PubMed

Evaluation of annexin A5 as a biomarker for Alzheimer's disease and dementia with lewy bodies

Hitoshi Sohma, Shin-ichi Imai, Norio Takei, Hirohito Honda, Kyoichi Matsumoto, Kumiko Utsumi, Kayo Matsuki, Eri Hashimoto, Toshikazu Saito, Yasuo Kokai

FRONTIERS IN AGING NEUROSCIENCE ( FRONTIERS RESEARCH FOUNDATION )  5   15  2013.04  [Refereed]

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Background: Alzheimer's disease (AD) differs from other forms of dementia in its relation to amyloid beta peptide (A beta(42)). Using a cell culture model we previously identified annexin A5, a Ca2+, and phospholipid binding protein, as an AD biomarker. Plasma level of annexin A5 was significantly higher in AD patients compared to that in a control group. On the other hand, AD has been identified to share a number of clinical and pathological features with Dementia with Lewy bodies (DLB). The present study was done to examine whether or not plasma annexin A5 is a specific marker for AD, when being compared with the levels of DLB patients. As Apolipoprotein E (ApoE) gene subtype epsilon 4 (ApoE-epsilon 4) has been noticed as the probable genetic factor for AD, we also examined and compared ApoE genotype in both AD and DLB. Methods: Blood samples were obtained from 150 patients with AD (aged 77.6 +/- 6.5 years), 50 patients of DLB (79.4 +/- 5.0) and 279 community-dwelling healthy elderly individuals of comparable age and sex (75.6 +/- 8.1). All AD patients met NINCDS-ADRDA criteria and all DLB patients were diagnosed as probable DLB according to the latest consensus diagnostic criteria. Quantification was done using the Chemiluminescent Enzyme Immunoassay (CLEIA) Technique (SphereLight assay) using the monoclonal antibodies against annexin A5. DNA genotyping of ApoE was performed by distinguishing unique combinations of Hha1 fragments of PCR-amplified genomic DNA products. Results: The plasma level of annexin A5 was significantly higher in AD patients than in the healthy individuals (control) (P < 0.0001). The plasma annexin A5 level was also significantly higher in DLB patients than in the control group (P < 0.0001). From the ROC curves with plasma annexin A5 concentrations, the mean areas under the curve were 0.863 and 0.838 for the AD/control and DLB/control, respectively. The rate of ApoE4 carrier status and the frequency of the epsilon 4 allele were significantly higher in AD or DLB than in control and there was no significant difference between AD and DLB. Conclusions: These results suggest that both annexin A5 and ApoE4 are common markers for AD and DLB.

DOI PubMed

Consideration from "Suicide report (2009~2011) by the National Police Agency of Japan"

木村 永一, 橋本 恵理

日本精神科病院協会雑誌 ( 日本精神科病院協会 )  32 ( 2 ) 167 - 172  2013.02

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A case of late onset consciousness disturbance due to lithium overdose

濱口 智大, 畠山 佳久, 吉川 徹, 畠山 茂樹, 橋本 恵理, 齋藤 利和

精神科 ( (有)科学評論社 )  22 ( 1 ) 121 - 125  2013.01

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50歳代女。20歳代で幻覚妄想状態で統合失調症を発症し、精神科病院へ入院した。退院後、週1回の訪問看護のもと単身生活を送っていたが、過量服薬をした可能性が高いと判断され、緊急搬送された。急性腎不全や横紋筋融解症などがあり、全身管理の必要性から転院となった。搬送時炭酸リチウムの血中濃度は2.54mEq/lと高値だったが、明らかな炭酸リチウムの中毒症状はなかった。意識障害などの中毒症状は認められず、精神状態は安定していた。第3病日夕方から意識レベルの動揺性を認めるようになり、しだいに痛み刺激にも反応しない状態となった。炭酸リチウムは、過量服薬の早期段階では、血中濃度が脳内濃度を反映しているとは限らず、注意深く経過を見ていく必要があることが示唆された。

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The Study of Cognitive Characteristics in Asperger's Disorder by Using a Modified Prisoner's Dilemma Game with a Variable Payoff Matrix

Masaya Tayama, Masaru Tateno, Tae Woo Park, Wataru Ukai, Eri Hashimoto, Toshikazu Saito

PLOS ONE ( PUBLIC LIBRARY SCIENCE )  7 ( 11 ) e48794  2012.11  [Refereed]

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Individuals with Asperger's Disorder (ASP) have difficulties in social reciprocity and in providing appropriate cooperative behavior. The Prisoner's Dilemma (PD) is a well-known model in game theory that illustrates the paradoxical disposition of interaction between two individuals with opposing interests, and may be a useful tool in the diagnosis of ASP in early childhood. In this study, we investigated the cognitive characteristics of ASP by using a modified PD game. The subjects were 29 individuals with ASP and 28 age-and IQ-matched controls. In the PD game, each of two players has two cards: card 1 represents cooperation and card 2 betrayal. The score each player obtains is decided according to a 2 x 2 payoff matrix and depends on the combination of their selections. The P-score ("P" for punishment) is defined as the score that is given when they both select betrayal. Comparing the two groups, the mean P-score at the end of the game and the mean total score were significantly higher in the ASP group, while the rate of selection of cooperative choice in both groups did not differ significantly. The classification of the shape of the graph according to fluctuation of the P-score revealed that in the ASP group only 2 cases (6.9%) showed continuous decrease of P-score compared to 8 control cases (28.6%) demonstrating similar results. However, the reasons were thought to be different: ASP subjects presumably selected card 2 because of a preference for the number itself, whereas control subjects preferentially chose this card to enhance their chance of winning the competition. It is often difficult to diagnose ASP in the young especially when they lack the distinctive clinical features of ASD in early childhood. Given the limited number of objective tools to evaluate the cognitive characteristics of ASP subjects, the PD game might be a useful diagnostic support tool for ASP.

DOI PubMed

Stem cell therapy: social recognition recovery in a FASD model.

Shirasaka T, Hashimoto E, Ukai W, Yoshinaga T, Ishii T, Tateno M, Saito T

Translational psychiatry   2   e188  2012.11  [Refereed]

DOI PubMed

Promising therapy of intravenous neural stem cell transplantation - A strategy for facilitation of neural network and behavioral recovery

Tomohiro Shirasaka, Wataru Ukai, Eri Hashimoto, Toshihiro Yoshinaga, Takao Ishii, Hiroo Kaneta, Toshikazu Saito

ASIA-PACIFIC PSYCHIATRY ( WILEY-BLACKWELL )  4   125 - 126  2012.10  [Refereed]

経静脈的神経幹細胞移植によるFASDモデルラットの行動異常改善と脳神経回路シナプス形成の修復

齋藤 利和, 鵜飼 渉, 白坂 知彦, 橋本 恵理, 吉永 敏弘, 金田 博雄, 五十嵐 健史, 渡邊 公彦, 館農 勝, 石井 貴男

アルコールと医学生物学 ( (株)響文社 )  31   40 - 40  2012.10

生物学的研究から新たな治療戦略へ アルコール・薬物依存に対する再生医療的アプローチ

橋本 恵理

日本アルコール関連問題学会雑誌 ( 日本アルコール関連問題学会 )  14 ( 2 ) 39 - 41  2012.09

アルコール・薬物依存 基礎から臨床まで アルコールによる脳障害に対する新たな治療法の可能性を探る FASDモデルを用いた検討

橋本 恵理, 白坂 知彦, 吉永 敏弘, 金田 博雄, 木川 昌康, 五十嵐 健史, 渡邊 公彦, 石井 貴男, 鵜飼 渉, 館農 勝, 齋藤 利和

日本アルコール・薬物医学会雑誌 ( (一社)日本アルコール・アディクション医学会 )  47 ( 4 ) 103 - 103  2012.08

Rhotekin modulates differentiation of cultured neural stem cells to neurons

Takashi Iwai, Akiyoshi Saitoh, Misa Yamada, Kou Takahashi, Eri Hashimoto, Wataru Ukai, Toshikazu Saito, Mitsuhiko Yamada

JOURNAL OF NEUROSCIENCE RESEARCH ( WILEY-BLACKWELL )  90 ( 7 ) 1359 - 1366  2012.07  [Refereed]

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Rhotekin is a downstream signal of Rho and is expressed in the central nervous system. However, the physiological role of rhotekin in the development of neural stem cells (NSCs) into neurons is unknown. In this study, we knocked down the expression of rhotekin protein with small interfering RNA (siRNA) in the NSCs and in neural differentiated cells and measured cell proliferation, differentiation, neurite length, and survival. By using immunocytochemistry and Western blot, the production of rhotekin was observed in NSCs and neuronal cells. Furthermore, rhotekin production was increased in accordance with neural differentiation. Rhotekin knock-down reduced 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) activity and increased the cell death 72 hr after transfection in neurons. On the other hand, in NSCs, rhotekin knock-down increased MTT activity and the number of 5-bromo-2'-deoxyuridine (BrdU)-positive cells. In the present study, we demonstrated that rhotekin is required for maintenance and survival of neurons and positively regulates differentiation and neurite outgrowth. Moreover, we found that rhotekin is produced in NSCs and that the role of rhotekin is to regulate cell proliferation negatively. In conclusion, these results suggest that rhotekin is one of the key molecules in the differentiation of NSCs into neurons. (c) 2012 Wiley Periodicals, Inc.

DOI PubMed

【統合失調症の病態研究から創薬への展開】統合失調症の脳神経回路修復 薬物・細胞コンバインド療法の可能性の検討

鵜飼 渉, 小野 貴文, 橋本 恵理, 金田 博雄, 白坂 知彦, 五十嵐 健史, 木川 昌康, 渡邊 公彦, 吉永 敏弘, 石井 貴男, 館農 勝, 小林 清樹, 齋藤 利和

日本生物学的精神医学会誌 ( 日本生物学的精神医学会 )  23 ( 2 ) 109 - 114  2012.06

東日本大震災で救助活動を行った消防隊員へのメンタルヘルス支援

小笠原 岳洋, 石川 博基, 橋本 恵理

日本森田療法学会雑誌 ( 日本森田療法学会 )  23 ( 1 ) 75 - 75  2012.04

Referral system for cooperation between a psychiatric clinic and a general hospital without a psychiatric service

石川 博基, 橋本 恵理, 館農 勝

日本精神科病院協会雑誌 ( 日本精神科病院協会 )  31 ( 4 ) 359 - 362  2012.04

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Heat stress activates ER stress signals which suppress the heat shock response, an effect occurring preferentially in the cortex in rats

Yaohua Liu, Hiroaki Sakamoto, Masaaki Adachi, Shiguang Zhao, Wataru Ukai, Eri Hashimoto, Masato Hareyama, Tadao Ishida, Kohzoh Imai, Yasuhisa Shinomura

MOLECULAR BIOLOGY REPORTS ( SPRINGER )  39 ( 4 ) 3987 - 3993  2012.04  [Refereed]

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Although heat stress induces a variety of illnesses, there have been few studies designed to uncover the molecular mechanisms underlining the illnesses. We here demonstrate that heat activates ER stress, which inhibits heat shock responses (HSR) via translational block. In heat-stressed rats, ER stress responses, as represented by eIF2 alpha phosphorylation and XBP1 splicing, occurred mainly in the cortex, where the HSR was substantially inhibited. Heat exposure also activated ER stress signals in primary cortical neurons. Since HSF1 knockdown enhanced heat-induced ER stress and subsequent cell death, HSR inhibition in turn augments ER stress, implying a vicious spiral of both stresses. Taken together, heat-induced ER stress impairs the HSR and enhances cell damage, thereby manifesting its unique effect on heat stress.

DOI PubMed

末梢BDNFは脳神経回路網変化にどう関わるか 血小板BDNF遊離機構に焦点を当てて

橋本 恵理, 鵜飼 渉, 渡邊 公彦, 白坂 知彦, 金田 博雄, 五十嵐 健史, 館農 勝, 吉永 敏弘, 齋藤 利和

精神薬療研究年報 ( (公財)先進医薬研究振興財団 )  ( 44 ) 67 - 68  2012.03

抗うつ薬関連遺伝子Rhotekinは神経分化を促進する

岩井 孝志, 斎藤 顕宜, 山田 美佐, 高橋 弘, 橋本 富男, 橋本 恵理, 鵜飼 渉, 齋藤 利和, 山田 光彦

国立精神・神経医療研究センター精神保健研究所年報 ( (国研)国立精神・神経医療研究センター精神保健研究所 )  ( 25 ) 233 - 233  2012.03

Reconstruction of neural network in schizophrenia ： Possible combined therapy of drugs and stem cells

Ukai Wataru, Ishii Takao, Tateno Masaru, Kobayashi Seiju, Saito Toshikazu, Ono Takafumi, Hashimoto Eri, Kaneta Hiroo, Shirasaka Tomohiro, Igarashi Takeshi, Kigawa Yoshiyasu, Watanabe Kimihiko, Yoshinaga Toshihiro

Japanese Journal of Biological Psychiatry ( 日本生物学的精神医学会 )  23 ( 2 ) 109 - 114  2012

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We constructed schizophrenia model rat by injection of Poly (I : C) in the maternal period. Animals in the Poly (I : C) treatment group showed a significant memory/cognitive impairment and social dysfunction in each behavioral test and intravenous neural stem cell transplantation suppressed these behavioral abnormalities toward control levels. The transplanted marked neural stem cells were detected in the various brain regions including cingulated cortex, hippocampus and amygdale over 6 months after the intravenous injection. Specifically, we detected the transplanted neural stem cells in hippocampus and amygdale which were positive with GAD protein suggesting the successful differentiation of transplanted cells into GABAergic neurons in these areas. Moreover, it was demonstrated that combined treatment of antipsychotic olanzapine promoted the migration/survival of transplanted neural stem cells in the brain. These results suggest that drug with stem cell transplantation must develop to a possible therapeutic approach for fetal and childhood stress related psychiatric disease such as schizophrenia and fetal alcohol spectrum disorder.

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Reconstruction of neural network in schizophrenia : Possible combined therapy of drugs and stem cells

鵜飼 渉, 小野 貴文, 橋本 恵理

日本生物学的精神医学会誌 = Japanese journal of biological psychiatry ( 日本生物学的精神医学会 ; 2010- )  23 ( 2 ) 109 - 114  2012

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Promising therapy of neural stem cell transplantation for FASD model : Neural network reconstruction and behavior recovery

SHIRASAKA Tomohiro, UKAI Wataru, YOSHINAGA Toshihiro, WATANABE Kimihiko, KANETA Hiroo, KIGAWA Yoshiyasu, IGARSHI Takeshi, TATENO Masaru, HASHIMOTO Eri, SAITO Toshikazu

日本アルコール・薬物医学会雑誌 = Japanese journal of alcohol studies & drug dependence ( (一社)日本アルコール・アディクション医学会 )  46 ( 6 ) 576 - 584  2011.12  [Domestic journal]

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OBJECTIVES: It has been elucidated that psychiatric disorders are associated with impairment of the brain neural network. Reduction in brain size and hypoplasia of the basal ganglia and corpus callosum have been reported in Fetal Alcohol Spectrum Disorder (FASD). It is believed that the formation of the neural network is influenced by alcohol exposure during the fetal period. Additionally, it is well known that the functional expression of CNS consequences of prenatal alcohol exposure includes cognitive and attentional processes, as well as social behavioral problems. It has also been reported that abnormal 5-HT neuron development can be reversed by treatment with a 5-HT1A agonist in a prenatal alcohol exposure model. However, these treatments are prophylactic. Without early intervention, the consequences of FASD are permanent. Recently, emerging evidence suggest that many clinical symptoms observed in psychiatric disease are likely related to neural network disruptions including neurogenesis dysfunction. Neural stem cell (NSC) transplantation has been investigated in areas such as brain injury, stroke and neurodegenerative diseases and may be a way to reverse neurogenesis dysfunction. In the present work, we evaluated the usefulness of intravenous transplantation of NSCs in the FASD model rat focusing on the possibility of regenerative therapy, particularly regarding behavioral abnormalities, for FASD rats. RESULTS: Abnormal behaviors FASD model rats suggest that reduced social activity , and cognitive dysfunction are major symptoms in FASD patients. Intravenous NSC transplantation appeared to partially correct these behavioral abnormalities in FASD model rats. In the Amygdala areas intravenous NSC transplantation appears to have partially regaenerates expression of PSD95 in FASD model rats. CONCLUSIONS: The results suggest that intravenous NSC transplantation may be an advanced approach to recover neural network damage and CNS dysfunction in FASD and possibly other psychiatric disorders.

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