Research activity information

• Oct. 2022 令和4年度 神戸大学医学部 優秀学術論文賞

  玉田 紘太


• Oct. 2009 日本生化学会, 日本生化学大会優秀プレゼンテーション賞

  玉田 紘太

• Duplication of the autism-related gene Chd8 leads to behavioral hyperactivity and neurodevelopmental defects in mice

  Atsuki Kawamura, Kazuki Fujii, Kota Tamada, Yoshifumi Abe, Kenta Nitahara, Tomoya Iwasaki, Sho Yagishita, Kenji F. Tanaka, Toru Takumi, Keizo Takao, Masaaki Nishiyama

  May 2025, Nature Communications

  [Refereed]

  Scientific journal


• Neurodevelopmental impact of CNV models in ASD: Recent advances and future directions.

  Kota Tamada, Toru Takumi

  Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social communication impairments and restricted, repetitive behaviors. ASD exhibits a strong genetic basis, with rare and common genetic variants contributing to its etiology. Copy number variations (CNVs), deletions or duplications of chromosomal segments, have emerged as key contributors to ASD risk. Rare CNVs often demonstrate large effect sizes and can directly cause ASD, while common variants collectively exert subtle influences. Recent advances have identified numerous ASD-associated CNVs, including recurrent loci such as 1q21.1, 2p16.3, 7q11.23, 15q11.2, 15q11-q13, 16p11.2 and 22q11.2. Mouse models carrying these CNVs have provided profound insights into the underlying neurobiological mechanisms. Recent studies integrating transcriptomic, proteomic, and functional imaging approaches have revealed alterations in synaptic function, neuronal differentiation, myelination, metabolic pathways, and circuit connectivity. Notably, investigations leveraging conditional knockout models, high magnetic field MRI, and single-cell analyses highlight disruptions in excitatory-inhibitory balance, white matter integrity, and dynamic gene regulatory networks. Parallel human-based approaches, including iPSC-derived neurons, cerebral organoids, and large-scale single-nucleus sequencing, are combined with animal model data. These integrative strategies promise to refine our understanding of ASD's genetic architecture, bridging the gap between fundamental discoveries in model organisms and clinically relevant biomarkers, subtypes, and therapeutic targets in humans. This review summarizes key findings from recent CNV mouse model studies and highlights emerging technologies applied to human ASD samples. Finally, we outline prospects for translating findings from mouse studies to humans. By illuminating both unique and convergent genetic mechanisms, these advances offer a critical framework for unraveling etiological complexity in ASD.

  Mar. 2025, Current opinion in neurobiology, 92, 103001 - 103001, English, International magazine

  [Refereed][Invited]

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• Prucalopride ameliorates delayed gastrointestinal transit and social behaviour in a mouse model of 15q duplication syndrome

  Gayathri K. Balasuriya, Kota Tamada, Jun Nomura, Carla Cirillo, Toru Takumi

  Abstract Introduction Chromosome 15q duplication syndrome (Dup15q) is a neurodevelopmental disorder linked to autism spectrum disorder (ASD), involving increased copies of the 15q11.2-q13 region. About 80% of individuals with Dup15q experience gastrointestinal (GI) dysfunction, including constipation. The duplicated region encodes GABA receptor A subunits, affecting GABAergic signalling, while reduced serotonin (5-HT) levels impair neuronal activity and social behaviour in a mouse model of Dup15q (15q dup). Given the importance of GABA and serotonin in the enteric nervous system (ENS), this study investigates GI dysfunction and neurotransmission in a Dup15q mouse model. Methods Colon RNA extracts were analysed for GABA receptor subunit and serotonin-associated gene expression using quantitative PCR. Total GI transit was assessed by Carmine red dye gavage. Ex vivo colonic motility was analysed via video imaging. The GABA receptor A antagonist Bicuculline was used to assess GABAergic signalling. Prucalopride, a 5-HT4 receptor (5HT4R) agonist, was administered for six days, and its effects on GI transit and social interaction were evaluated. Results 15q dup mice exhibited elevated GABA receptor gene expression and reduced Tph2 and Htr4 expression in the colon. Total GI transit was delayed, and ex vivo colonic motility was slower and less extensive. Bicuculline further impaired colonic contractions, indicating enhanced GABAergic sensitivity. Prucalopride restored GI transit delays and improved social interaction, as evidenced by increased contact duration in social tests. Conclusion Prucalopride effectively restores GI function and improves social behaviour in 15q dup mice, demonstrating its therapeutic potential for addressing both GI dysfunction and behavioural deficits in 15q duplication syndrome.

  Cold Spring Harbor Laboratory, Mar. 2025, BioRxiv


• Remodeling of the postsynaptic proteome in male mice and marmosets during synapse development.

  Takeshi Kaizuka, Takehiro Suzuki, Noriyuki Kishi, Kota Tamada, Manfred W Kilimann, Takehiko Ueyama, Masahiko Watanabe, Tomomi Shimogori, Hideyuki Okano, Naoshi Dohmae, Toru Takumi

  Abstract Postsynaptic proteins play crucial roles in synaptic function and plasticity. During brain development, alterations in synaptic number, shape, and stability occur, known as synapse maturation. However, the postsynaptic protein composition changes during development are not fully understood. Here, we show the trajectory of the postsynaptic proteome in developing male mice and common marmosets. Proteomic analysis of mice at 2, 3, 6, and 12 weeks of age shows that proteins involved in synaptogenesis are differentially expressed during this period. Analysis of published transcriptome datasets shows that the changes in postsynaptic protein composition in the mouse brain after 2 weeks of age correlate with gene expression changes. Proteomic analysis of marmosets at 0, 2, 3, 6, and 24 months of age show that the changes in the marmoset brain can be categorized into two parts: the first 2 months and after that. The changes observed in the first 2 months are similar to those in the mouse brain between 2 and 12 weeks of age. The changes observed in marmoset after 2 months old include differential expression of synaptogenesis-related molecules, which hardly overlap with that in mice. Our results provide a comprehensive proteomic resource that underlies developmental synapse maturation in rodents and primates.

  Springer Science and Business Media LLC, Mar. 2024, Nature communications, 15(1) (1), 2496 - 2496, English, International magazine

  [Refereed]

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• Large-scale animal model study uncovers altered brain pH and lactate levels as a transdiagnostic endophenotype of neuropsychiatric disorders involving cognitive impairment.

  Hideo Hagihara, Hirotaka Shoji, Satoko Hattori, Giovanni Sala, Yoshihiro Takamiya, Mika Tanaka, Masafumi Ihara, Mihiro Shibutani, Izuho Hatada, Kei Hori, Mikio Hoshino, Akito Nakao, Yasuo Mori, Shigeo Okabe, Masayuki Matsushita, Anja Urbach, Yuta Katayama, Akinobu Matsumoto, Keiichi I Nakayama, Shota Katori, Takuya Sato, Takuji Iwasato, Haruko Nakamura, Yoshio Goshima, Matthieu Raveau, Tetsuya Tatsukawa, Kazuhiro Yamakawa, Noriko Takahashi, Haruo Kasai, Johji Inazawa, Ikuo Nobuhisa, Tetsushi Kagawa, Tetsuya Taga, Mohamed Darwish, Hirofumi Nishizono, Keizo Takao, Kiran Sapkota, Kazutoshi Nakazawa, Tsuyoshi Takagi, Haruki Fujisawa, Yoshihisa Sugimura, Kyosuke Yamanishi, Lakshmi Rajagopal, Nanette Deneen Hannah, Herbert Y Meltzer, Tohru Yamamoto, Shuji Wakatsuki, Toshiyuki Araki, Katsuhiko Tabuchi, Tadahiro Numakawa, Hiroshi Kunugi, Freesia L Huang, Atsuko Hayata-Takano, Hitoshi Hashimoto, Kota Tamada, Toru Takumi, Takaoki Kasahara, Tadafumi Kato, Isabella A Graef, Gerald R Crabtree, Nozomi Asaoka, Hikari Hatakama, Shuji Kaneko, Takao Kohno, Mitsuharu Hattori, Yoshio Hoshiba, Ryuhei Miyake, Kisho Obi-Nagata, Akiko Hayashi-Takagi, Léa J Becker, Ipek Yalcin, Yoko Hagino, Hiroko Kotajima-Murakami, Yuki Moriya, Kazutaka Ikeda, Hyopil Kim, Bong-Kiun Kaang, Hikari Otabi, Yuta Yoshida, Atsushi Toyoda, Noboru H Komiyama, Seth G N Grant, Michiru Ida-Eto, Masaaki Narita, Ken-Ichi Matsumoto, Emiko Okuda-Ashitaka, Iori Ohmori, Tadayuki Shimada, Kanato Yamagata, Hiroshi Ageta, Kunihiro Tsuchida, Kaoru Inokuchi, Takayuki Sassa, Akio Kihara, Motoaki Fukasawa, Nobuteru Usuda, Tayo Katano, Teruyuki Tanaka, Yoshihiro Yoshihara, Michihiro Igarashi, Takashi Hayashi, Kaori Ishikawa, Satoshi Yamamoto, Naoya Nishimura, Kazuto Nakada, Shinji Hirotsune, Kiyoshi Egawa, Kazuma Higashisaka, Yasuo Tsutsumi, Shoko Nishihara, Noriyuki Sugo, Takeshi Yagi, Naoto Ueno, Tomomi Yamamoto, Yoshihiro Kubo, Rie Ohashi, Nobuyuki Shiina, Kimiko Shimizu, Sayaka Higo-Yamamoto, Katsutaka Oishi, Hisashi Mori, Tamio Furuse, Masaru Tamura, Hisashi Shirakawa, Daiki X Sato, Yukiko U Inoue, Takayoshi Inoue, Yuriko Komine, Tetsuo Yamamori, Kenji Sakimura, Tsuyoshi Miyakawa

  Increased levels of lactate, an end-product of glycolysis, have been proposed as a potential surrogate marker for metabolic changes during neuronal excitation. These changes in lactate levels can result in decreased brain pH, which has been implicated in patients with various neuropsychiatric disorders. We previously demonstrated that such alterations are commonly observed in five mouse models of schizophrenia, bipolar disorder, and autism, suggesting a shared endophenotype among these disorders rather than mere artifacts due to medications or agonal state. However, there is still limited research on this phenomenon in animal models, leaving its generality across other disease animal models uncertain. Moreover, the association between changes in brain lactate levels and specific behavioral abnormalities remains unclear. To address these gaps, the International Brain pH Project Consortium investigated brain pH and lactate levels in 109 strains/conditions of 2294 animals with genetic and other experimental manipulations relevant to neuropsychiatric disorders. Systematic analysis revealed that decreased brain pH and increased lactate levels were common features observed in multiple models of depression, epilepsy, Alzheimer's disease, and some additional schizophrenia models. While certain autism models also exhibited decreased pH and increased lactate levels, others showed the opposite pattern, potentially reflecting subpopulations within the autism spectrum. Furthermore, utilizing large-scale behavioral test battery, a multivariate cross-validated prediction analysis demonstrated that poor working memory performance was predominantly associated with increased brain lactate levels. Importantly, this association was confirmed in an independent cohort of animal models. Collectively, these findings suggest that altered brain pH and lactate levels, which could be attributed to dysregulated excitation/inhibition balance, may serve as transdiagnostic endophenotypes of debilitating neuropsychiatric disorders characterized by cognitive impairment, irrespective of their beneficial or detrimental nature.

  Mar. 2024, eLife, 12, English, International magazine

  [Refereed]

  Scientific journal


• The East Asian-Specific Risk Genes in Autism Spectrum Disorder.

  Kota Tamada, Toru Takumi

  Lead, Nov. 2023, Biological psychiatry, 94(10) (10), 762 - 764, English, International magazine

  [Invited]

  Scientific journal


• An old model with new insights: endogenous retroviruses drive the evolvement toward ASD susceptibility and hijack transcription machinery during development.

  Chia-Wen Lin, Jacob Ellegood, Kota Tamada, Ikuo Miura, Mikiko Konda, Kozue Takeshita, Koji Atarashi, Jason P Lerch, Shigeharu Wakana, Thomas J McHugh, Toru Takumi

  The BTBR T+Itpr3tf/J (BTBR/J) strain is one of the most valid models of idiopathic autism, serving as a potent forward genetics tool to dissect the complexity of autism. We found that a sister strain with an intact corpus callosum, BTBR TF/ArtRbrc (BTBR/R), showed more prominent autism core symptoms but moderate ultrasonic communication/normal hippocampus-dependent memory, which may mimic autism in the high functioning spectrum. Intriguingly, disturbed epigenetic silencing mechanism leads to hyperactive endogenous retrovirus (ERV), a mobile genetic element of ancient retroviral infection, which increases de novo copy number variation (CNV) formation in the two BTBR strains. This feature makes the BTBR strain a still evolving multiple-loci model toward higher ASD susceptibility. Furthermore, active ERV, analogous to virus infection, evades the integrated stress response (ISR) of host defense and hijacks the transcriptional machinery during embryonic development in the BTBR strains. These results suggest dual roles of ERV in the pathogenesis of ASD, driving host genome evolution at a long-term scale and managing cellular pathways in response to viral infection, which has immediate effects on embryonic development. The wild-type Draxin expression in BTBR/R also makes this substrain a more precise model to investigate the core etiology of autism without the interference of impaired forebrain bundles as in BTBR/J.

  May 2023, Molecular psychiatry, 28(5) (5), 1932 - 1945, English, International magazine

  [Refereed]

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• A common epigenetic mechanism across different cellular origins underlies systemic immune dysregulation in an idiopathic autism mouse model.

  Chia-Wen Lin, Dian E Septyaningtrias, Hsu-Wen Chao, Mikiko Konda, Koji Atarashi, Kozue Takeshita, Kota Tamada, Jun Nomura, Yohei Sasagawa, Kaori Tanaka, Itoshi Nikaido, Kenya Honda, Thomas J McHugh, Toru Takumi

  Immune dysregulation plays a key role in the pathogenesis of autism. Changes occurring at the systemic level, from brain inflammation to disturbed innate/adaptive immune in the periphery, are frequently observed in patients with autism; however, the intrinsic mechanisms behind them remain elusive. We hypothesize a common etiology may lie in progenitors of different types underlying widespread immune dysregulation. By single-cell RNA sequencing (sc-RNA seq), we trace the developmental origins of immune dysregulation in a mouse model of idiopathic autism. It is found that both in aorta-gonad-mesonephros (AGM) and yolk sac (YS) progenitors, the dysregulation of HDAC1-mediated epigenetic machinery alters definitive hematopoiesis during embryogenesis and downregulates the expression of the AP-1 complex for microglia development. Subsequently, these changes result in the dysregulation of the immune system, leading to gut dysbiosis and hyperactive microglia in the brain. We further confirm that dysregulated immune profiles are associated with specific microbiota composition, which may serve as a biomarker to identify autism of immune-dysregulated subtypes. Our findings elucidate a shared mechanism for the origin of immune dysregulation from the brain to the gut in autism and provide new insight to dissecting the heterogeneity of autism, as well as the therapeutic potential of targeting immune-dysregulated autism subtypes.

  Aug. 2022, Molecular psychiatry, 27(8) (8), 3343 - 3354, English, International magazine

  [Refereed]

  Scientific journal


• Increased self-triggered vocalizations in an epidermal growth factor-induced rat model for schizophrenia.

  Itaru Narihara, Hanako Yokoyama, Hisaaki Namba, Hidekazu Sotoyama, Hiroyoshi Inaba, Eiko Kitayama, Kota Tamada, Toru Takumi, Hiroyuki Nawa

  Abstract Rats elicit two types of ultrasonic vocalizations (USVs), positive (30–80 kHz; high pitch) and negative (10–30 kHz; low pitch) voices. As patients with schizophrenia often exhibit soliloquy-like symptoms, we explored whether an animal model for schizophrenia is similarly characterized by such self-triggered vocalizations. We prepared the animal model by administering an inflammatory cytokine, epidermal growth factor (EGF), to rat neonates, which later develop behavioral and electroencephalographic deficits relevant to schizophrenia. EGF model rats and controls at young (8–10 weeks old) and mature (12–14 weeks old) adult stages were subjected to acclimation, female pairing, and vocalization sessions. In acclimation sessions, low pitch USVs at the mature adult stage were more frequent in EGF model rats than in controls. In the vocalization session, the occurrences of low pitch self-triggered USVs were higher in EGF model rats in both age groups, although this group difference was eliminated by their risperidone treatment. Unlike conventional negative USVs of rats, however, the present low pitch self-triggered USVs had short durations of 10–30 ms. These results suggest the potential that self-triggered vocalization might serve as a translatable pathological trait of schizophrenia to animal models.

  Springer Science and Business Media LLC, Jul. 2022, Scientific reports, 12(1) (1), 12917 - 12917, English, International magazine

  [Refereed]

  Scientific journal


• Sensing the Sounds of Silence: A Pilot Study on the Detection of Model Mice of Autism Spectrum Disorder from Ultrasonic Vocalisations.

  Kun Qian, Tomoya Koike, Kota Tamada, Toru Takumi, Bjorn W Schuller, Yoshiharu Yamamoto

  Studying the animal models of human neuropsychiatric disorders can facilitate the understanding of mechanisms of symptoms both physiologically and genetically. Previous studies have shown that ultrasonic vocalisations (USVs) of mice might be efficient markers to distinguish the wild type group and the model of autism spectrum disorder (mASD). Nevertheless, in-depth analysis of these 'silence' sounds by leveraging the power of advanced computer audition technologies (e. g., deep learning) is limited. To this end, we propose a pilot study on using a large-scale pre-trained audio neural network to extract high-level representations from the USVs of mice for the task on detection of mASD. Experiments have shown a best result reaching an unweighted average recall of 79.2 % for the binary classification task in a rigorous subject-independent scenario. To the best of our knowledge, this is the first time to analyse the sounds that cannot be heard by human beings for the detection of mASD mice. The novel findings can be significant to motivate future works with according means on studying animal models of human patients.

  Nov. 2021, Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference, 2021, 68 - 71, English, International magazine

  [Refereed]

  Scientific journal


• Genetic dissection identifies Necdin as a driver gene in a mouse model of paternal 15q duplications.

  Kota Tamada, Keita Fukumoto, Tsuyoshi Toya, Nobuhiro Nakai, Janak R Awasthi, Shinji Tanaka, Shigeo Okabe, François Spitz, Fumihito Saitow, Hidenori Suzuki, Toru Takumi

  Maternally inherited duplication of chromosome 15q11-q13 (Dup15q) is a pathogenic copy number variation (CNV) associated with autism spectrum disorder (ASD). Recently, paternally derived duplication has also been shown to contribute to the development of ASD. The molecular mechanism underlying paternal Dup15q remains unclear. Here, we conduct genetic and overexpression-based screening and identify Necdin (Ndn) as a driver gene for paternal Dup15q resulting in the development of ASD-like phenotypes in mice. An excess amount of Ndn results in enhanced spine formation and density as well as hyperexcitability of cortical pyramidal neurons. We generate 15q dupΔNdn mice with a normalized copy number of Ndn by excising its one copy from Dup15q mice using a CRISPR-Cas9 system. 15q dupΔNdn mice do not show ASD-like phenotypes and show dendritic spine dynamics and cortical excitatory-inhibitory balance similar to wild type animals. Our study provides an insight into the role of Ndn in paternal 15q duplication and a mouse model of paternal Dup15q syndrome.

  Lead, Jul. 2021, Nature communications, 12(1) (1), 4056 - 4056, English, International magazine

  [Refereed]

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• Cranioplastic Surgery and Acclimation Training for Awake Mouse fMRI

  Tomokazu Tsurugizawa, Kota Tamada, Clement Debacker, Andrew Zalesky, Toru Takumi

  MRI is a promising tool for translational research to link brain function and structure in animal models of disease to patients with neuropsychiatric disorders. However, given that mouse functional MRI (fMRI) typically relies on anesthetics to suppress head motion and physiological noise, it has been difficult to directly compare brain fMRI in anesthetized mice with that in conscious patients. Here, we developed a new system to acquire fMRI in awake mice, which includes a head positioner and dedicated radio frequency coil. The system was used to investigate functional brain networks in conscious mice, with the goal of enabling future studies to bridge fMRI of disease model animals with human fMRI. Cranioplastic surgery was performed to affix the head mount and the cupped-hand handling method was performed to minimize stress during MRI scanning. Here we describe the new mouse fMRI system, cranioplastic surgery and acclimation protocol. Graphic abstract: Awake fMRI system to investigate the neuronal activity in awaked mice.

  Bio-Protocol, LLC, 2021, BIO-PROTOCOL, 11(7) (7), e3972, English, International magazine

  [Refereed]

  Scientific journal


• Altered microbiota composition reflects enhanced communication in 15q11-13 CNV mice.

  Dian Eurike Septyaningtrias, Chia-Wen Lin, Rika Ouchida, Nobuhiro Nakai, Wataru Suda, Masahira Hattori, Hidetoshi Morita, Kenya Honda, Kota Tamada, Toru Takumi

  Autism spectrum disorder (ASD) is a complex and heterogeneous neurodevelopmental disorder. In addition to the core symptoms of ASD, many patients with ASD also show comorbid gut dysbiosis, which may lead to various gastrointestinal (GI) problems. Intriguingly, there is evidence that gut microbiota communicate with the central nervous system to modulate behavioral output through the gut-brain axis. To investigate how the microbiota composition is changed in ASD and to identify which microbes are involved in autistic behaviors, we performed a 16S rRNA gene-based metagenomics analysis in an ASD mouse model. Here, we focused on a model with human 15q11-13 duplication (15q dup), the most frequent chromosomal aberration or copy number variation found in ASD. Species diversity of the microbiome was significantly decreased in 15q dup mice. A combination of antibiotics treatment and behavioral analysis showed that neomycin improved social communication in 15q dup mice. Furthermore, comparison of the microbiota composition of mice treated with different antibiotics enabled us to identify beneficial operational taxonomic units (OTUs) for ultrasonic vocalization.

  Dec. 2020, Neuroscience research, 161, 59 - 67, English, International magazine

  [Refereed]

  Scientific journal


• Development of serotonergic projections to the suprachiasmatic nucleus in the mouse brain.

  Janak R Awasthi, Kota Tamada, Eric T N Overton, Toru Takumi

  Serotonin (5-HT) and its innervation have been implicated in various neural functions including circadian systems. Although classical studies have examined the 5-HT innervation pattern in the adult suprachiasmatic nucleus (SCN), the fine-grained morphological study of the development of pathway and terminal projections to the SCN remains scarce. Here, we utilize transgenic mice expressing GFP under the serotonin transporter (SERT) promoter to subserve our developmental mapping study. We demonstrate that the morphology of 5-HT pathway fibers decussating over the supraoptic commissure that projects to the SCN exhibits two distinct developmental patterns. The punctate fibers at the fetal stage gradually become smooth and filamentous, especially during postnatal one week and remain constant thereafter. The innervation field in the SCN develops properly only during postnatal two weeks. Its ventromedial area remains one of the highest 5-HT innervated areas in the adult brain, whereas the dorsolateral area is less innervated. Thus, we provide novel and specific insights on the developmental map of 5-HT system into the SCN using transgenic mouse.

  Nov. 2020, Neuroscience letters, 739, 135438 - 135438, English, International magazine

  [Refereed]

  Scientific journal


• Comprehensive topographical map of the serotonergic fibers in the male mouse brain.

  Janak R Awasthi, Kota Tamada, Eric T N Overton, Toru Takumi

  It is well established that serotonergic fibers distribute throughout the brain. Abnormal densities or patterns of serotonergic fibers have been implicated in neuropsychiatric disorders. Although many classical studies have examined the distribution pattern of serotonergic fibers, most of them were either limited to specific brain areas or had limitations in demonstrating the fine axonal morphology. In this study, we utilize male mice expressing green fluorescence protein under the serotonin transporter (SERT) promoter to map the topography of serotonergic fibers across the rostro-caudal extent of each brain area. We demonstrate previously unreported regional density and fine-grained anatomy of serotonergic fibers. Our findings include: (a) SERT fibers distribute abundantly in the thalamic nuclei close to the midline and dorsolateral areas, in most of the hypothalamic nuclei with few exceptions such as the median eminence and arcuate nuclei, and within the basal amygdaloid complex and lateral septal nuclei, (b) the source fibers of innervation of the hippocampus traverse through the septal nuclei before reaching its destination, (c) unique, filamentous type of straight terminal fibers within the nucleus accumbens, (d) laminar pattern of innervation in the hippocampus, olfactory bulb and cortex with heterogenicity in innervation density among the layers, (e) cortical labeling density gradually decreases rostro-caudally, (f) fibers traverse and distribute mostly within the gray matter, leaving the white fiber bundles uninnervated, and (g) most of the highly labeled nuclei and cortical areas have predominant anatomical connection to limbic structures. In conclusion, we provide novel, regionally specific insights on the distribution map of serotonergic fibers using transgenic mouse.

  Sep. 2020, The Journal of comparative neurology, 529(7) (7), 1391 - 1429, English, International magazine

  [Refereed]

  Scientific journal


• Behavioral neuroscience of autism.

  Toru Takumi, Kota Tamada, Fumiyuki Hatanaka, Nobuhiro Nakai, Patrick F Bolton

  Autism spectrum disorder (ASD) is a neurodevelopmental disorder. Several genetic causes of ASD have been identified and this has enabled researchers to construct mouse models. Mouse behavioral tests reveal impaired social interaction and communication, as well as increased repetitive behavior and behavioral inflexibility in these mice, which correspond to core behavioral deficits observed in individuals with ASD. However, the connection between these behavioral abnormalities and the underlying dysregulation in neuronal circuits and synaptic function is poorly understood. Moreover, different components of the ASD phenotype may be linked to dysfunction in different brain regions, making it even more challenging to chart the pathophysiological mechanisms involved in ASD. Here we summarize the research on mouse models of ASD and their contribution to understanding pathophysiological mechanisms. Specifically, we emphasize abnormal serotonin production and regulation, as well as the disruption in circadian rhythms and sleep that are observed in a subset of ASD, and propose that spatiotemporal disturbances in brainstem development may be a primary cause of ASD that propagates towards the cerebral cortex.

  Mar. 2020, Neuroscience and biobehavioral reviews, 110, 60 - 76, English, International magazine, Co-authored internationally

  [Refereed]

  Scientific journal


• Awake functional MRI detects neural circuit dysfunction in a mouse model of autism.

  Tomokazu Tsurugizawa, Kota Tamada, Nobukazu Ono, Sachise Karakawa, Yuko Kodama, Clement Debacker, Junichi Hata, Hideyuki Okano, Akihiko Kitamura, Andrew Zalesky, Toru Takumi

  MRI has potential as a translational approach from rodents to humans. However, given that mouse functional MRI (fMRI) uses anesthetics for suppression of motion, it has been difficult to directly compare the result of fMRI in "unconsciousness" disease model mice with that in "consciousness" patients. We develop awake fMRI to investigate brain function in 15q dup mice, a copy number variation model of autism. Compared to wild-type mice, we find that 15q dup is associated with whole-brain functional hypoconnectivity and diminished fMRI responses to odors of stranger mice. Ex vivo diffusion MRI reveals widespread anomalies in white matter ultrastructure in 15q dup mice, suggesting a putative anatomical substrate for these functional hypoconnectivity. We show that d-cycloserine (DCS) treatment partially normalizes these anormalies in the frontal cortex of 15q dup mice and rescues some social behaviors. Our results demonstrate the utility of awake rodent fMRI and provide a rationale for further investigation of DCS therapy.

  Feb. 2020, Science advances, 6(6) (6), eaav4520, English, International magazine, Co-authored internationally

  [Refereed]

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• Behavioral analysis in mice deficient for GAREM2 (Grb2-associated regulator of Erk/MAPK subtype2) that is a subtype of highly expressing in the brain.

  Tasuku Nishino, Kota Tamada(equally contributed), Akane Maeda, Takaya Abe, Hiroshi Kiyonari, Yasuhiro Funahashi, Kozo Kaibuchi, Toru Takumi, Hiroaki Konishi

  Grb2-associated regulator of Erk/MAPK (GAREM), is an adaptor protein related to the several cell growth factor receptor-signaling. The GAREM family has two subtypes, GAREM1 and GAREM2, both encoded in the human and mouse genome. Recent genome-wide research identified GAREM2 as a candidate of neurodegenerative diseases. Here, we use knockout (KO) mice to show the role of GAREM2, that is highly expressed in the brain. According to the comprehensive behavioral battery, they exhibited less anxiety both in elevated plus maze and open field tests, mildly increased social approaching behavior in the reciprocal social interaction test, and longer latency to immobility in the tail suspension test as compared to wild-type (WT). Additionally, the extension of neurites in the primary cultured neurons was suppressed in ones derived from GAREM2 KO mice. Furthermore, we also identified Intersectin, as a binding partner of GAREM2 in this study. Intersectin is also a multi-domain adaptor protein that regulates endocytosis and cell signaling, which can potentially alter the subcellular localization of GAREM2. The important molecules, such as the neurotrophin receptor and Erk family, that are involved in the signaling pathway of the neural cell growth in the mouse brain, have been reported to participate in emotional behavior. As GAREM plays a role in the cellular growth factor receptor signaling pathway, GAREM2 may have a common role related to the transduction of Erk signaling in the higher brain functions.

  Lead, Nov. 2019, Molecular brain, 12(1) (1), 94 - 94, English, International magazine

  [Refereed]

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• UBE3A regulates the transcription of IRF, an antiviral immunity.

  Ryohei Furumai, Kota Tamada, Xiaoxi Liu, Toru Takumi

  UBE3A is a gene responsible for the pathogenesis of Angelman syndrome (AS), a neurodevelopmental disorder characterized by symptoms such as intellectual disability, delayed development and severe speech impairment. UBE3A encodes an E3 ubiquitin ligase, for which several targets have been identified, including synaptic molecules. Although proteolysis mainly occurs in the cytoplasm, UBE3A is localized to the cytoplasm and the nucleus. In fact, UBE3A is also known as a transcriptional regulator of the family of nuclear receptors. However, the function of UBE3A in the nucleus remains unclear. Therefore, we examined the involvement of UBE3A in transcription in the nuclei of neurons. Genome-wide transcriptome analysis revealed an enrichment of genes downstream of interferon regulatory factor (IRF) in a UBE3A-deficient AS mouse model. In vitro biochemical analyses further demonstrated that UBE3A interacted with IRF and, more importantly, that UBE3A enhanced IRF-dependent transcription. These results suggest a function for UBE3A as a transcriptional regulator of the immune system in the brain. These findings also provide informative molecular insights into the function of UBE3A in the brain and in AS pathogenesis.

  Jun. 2019, Human molecular genetics, 28(12) (12), 1947 - 1958, English, International magazine

  [Refereed]

  Scientific journal


• Gene expression profile data of the developing small intestine of Id2-deficient mice.

  Kentaro Mori, Kota Tamada, Hisanori Kurooka, Makoto Matsui, Toru Takumi, Yoshifumi Yokota

  This article contains data related to the research article entitled "Id2 determines intestinal identity through repression of the foregut transcription factor, Irx5" [1]. Id2 deficient (Id2-/-) mice developed gastric tumors and heterotopic squamous epithelium in the small intestine. These tumors and heterotopic tissues were derived from ectopic gastric cells and squamous cells formed in the small intestine respectively during development. In this study, microarray data of the developing small intestine of Id2-/- mice was analyzed.

  Jun. 2019, Data in brief, 24, 103717 - 103717, English, International magazine

  [Refereed]

  Scientific journal


• Identification of genes regulating GABAergic interneuron maturation.

  Keita Fukumoto, Kota Tamada(equally contributed), Tsuyoshi Toya, Tasuku Nishino, Yuchio Yanagawa, Toru Takumi

  During embryonic development, GABAergic interneurons, a main inhibitory component in the cerebral cortex, migrate tangentially from the ganglionic eminence (GE) to cerebral cortex. After reaching the cerebral cortex, they start to extend their neurites for constructing local neuronal circuits around the neonatal stage. Aberrations in migration or neurite outgrowth are implicated in neurological and psychiatric disorders such as epilepsy, schizophrenia and autism. Previous studies revealed that in the early phase of cortical development the neural population migrates tangentially from the GE in the telencephalon and several genes have been characterized as regulators of migration and specification of GABAergic interneurons. However, much less is known about the molecular mechanisms of GABAergic interneurons-specific maturation at later stages of development. Here, we performed genome-wide screening to identify genes related to the later stage by flow cytometry based-microarray (FACS-array) and identified 247 genes expressed in cortical GABAergic interneurons. Among them, Dgkg, a member of diacylglycerol kinase family, was further analyzed. Correlational analysis revealed that Dgkg is dominantly expressed in somatostatin (SST)-expressing GABAergic interneurons. The functional study of Dgkg using GE neurons indicated alteration in neurite outgrowth of GABAergic neurons. This study shows a new functional role for Dgkg in GABAergic interneurons as well as the identification of other candidate genes for their maturation.

  Lead, Sep. 2018, Neuroscience research, 134, 18 - 29, English, International magazine

  [Refereed]

  Scientific journal


• Id2 Determines Intestinal Identity through Repression of the Foregut Transcription Factor Irx5.

  Kentaro Mori, Harumi Nakamura, Hisanori Kurooka, Hitoshi Miyachi, Kota Tamada, Manabu Sugai, Toru Takumi, Yoshifumi Yokota

  The cellular components and function of the gastrointestinal epithelium exhibit distinct characteristics depending on the region, e.g., stomach or intestine. How these region-specific epithelial characteristics are generated during development remains poorly understood. Here, we report on the involvement of the helix-loop-helix inhibitor Id2 in establishing the specific characteristics of the intestinal epithelium. Id2-/- mice developed tumors in the small intestine. Histological analysis indicated that the intestinal tumors were derived from gastric metaplasia formed in the small intestine during development. Heterotopic Id2 expression in developing gastric epithelium induced a fate change to intestinal epithelium. Gene expression analysis revealed that foregut-enriched genes encoding Irx3 and Irx5 were highly induced in the midgut of Id2-/- embryos, and transgenic mice expressing Irx5 in the midgut endoderm developed tumors recapitulating the characteristics of Id2-/- mice. Altogether, our results demonstrate that Id2 plays a crucial role in the development of regional specificity in the gastrointestinal epithelium.

  May 2018, Molecular and cellular biology, 38(9) (9), English, International magazine

  [Refereed]

  Scientific journal


• CNV biology in neurodevelopmental disorders.

  Toru Takumi, Kota Tamada

  Elsevier Ltd, Feb. 2018, Current opinion in neurobiology, 48, 183 - 192, English, International magazine

  [Refereed]

  Scientific journal


• Functional significance of rare neuroligin 1 variants found in autism

  Moe Nakanishi, Jun Nomura, Xiao Ji, Kota Tamada, Takashi Arai, Eiki Takahashi, Maja Bucan, Toru Takumi

  Aug. 2017, PLOS GENETICS, 13(8) (8), English, Co-authored internationally

  [Refereed]

  Scientific journal


• Serotonin rebalances cortical tuning and behavior linked to autism symptoms in 15q11-13 CNV mice.

  Nobuhiro Nakai, Masatoshi Nagano, Fumihito Saitow, Yasuhito Watanabe, Yoshinobu Kawamura, Akiko Kawamoto, Kota Tamada, Hiroshi Mizuma, Hirotaka Onoe, Yasuyoshi Watanabe, Hiromu Monai, Hajime Hirase, Jin Nakatani, Hirofumi Inagaki, Tomoyuki Kawada, Taisuke Miyazaki, Masahiko Watanabe, Yuka Sato, Shigeo Okabe, Kazuo Kitamura, Masanobu Kano, Kouichi Hashimoto, Hidenori Suzuki, Toru Takumi

  Jun. 2017, Science advances, 3(6) (6), e1603001, English, International magazine

  [Refereed]

  Scientific journal


• Behavioral and neuroanatomical analyses in a genetic mouse model of 2q13 duplication.

  Keiko Kishimoto, Jun Nomura, Jacob Ellegood, Keita Fukumoto, Jason P Lerch, Daniel Moreno-De-Luca, Thomas Bourgeron, Kota Tamada, Toru Takumi

  May 2017, Genes to cells : devoted to molecular & cellular mechanisms, 22(5) (5), 436 - 451, English, International magazine, Co-authored internationally

  [Refereed]

  Scientific journal


• Ror2 signaling regulates Golgi structure and transport through IFT20 for tumor invasiveness.

  Michiru Nishita, Seung-Yeol Park, Tadashi Nishio, Koki Kamizaki, ZhiChao Wang, Kota Tamada, Toru Takumi, Ryuju Hashimoto, Hiroki Otani, Gregory J Pazour, Victor W Hsu, Yasuhiro Minami

  Signaling through the Ror2 receptor tyrosine kinase promotes invadopodia formation for tumor invasion. Here, we identify intraflagellar transport 20 (IFT20) as a new target of this signaling in tumors that lack primary cilia, and find that IFT20 mediates the ability of Ror2 signaling to induce the invasiveness of these tumors. We also find that IFT20 regulates the nucleation of Golgi-derived microtubules by affecting the GM130-AKAP450 complex, which promotes Golgi ribbon formation in achieving polarized secretion for cell migration and invasion. Furthermore, IFT20 promotes the efficiency of transport through the Golgi complex. These findings shed new insights into how Ror2 signaling promotes tumor invasiveness, and also advance the understanding of how Golgi structure and transport can be regulated.

  Jan. 2017, Scientific reports, 7(1) (1), 1 - 1, English, International magazine, Co-authored internationally

  [Refereed]

  Scientific journal


• Erratum: Correction: Functional significance of rare neuroligin 1 variants found in autism (PLoS genetics (2017) 13 8 (e1006940))

  Nakanishi, M., Nomura, J., Ji, X., Tamada, K., Arai, T., Takahashi, E., Bu?an, M., Takumi, T.

  2017, PLoS genetics, 13(10) (10)

  Scientific journal


• Transcriptome profiling of white adipose tissue in a mouse model for 15q duplication syndrome.

  Xiaoxi Liu, Kota Tamada(equally contributed), Rui Kishimoto, Hiroko Okubo, Satoko Ise, Hisashi Ohta, Sandra Ruf, Jin Nakatani, Nobuoki Kohno, François Spitz, Toru Takumi

  Lead, Elsevier Inc, Sep. 2015, Genomics data, 5, 394 - 6, English, International magazine, Co-authored internationally

  [Refereed]

  Scientific journal


• Model mice for 15q11-13 duplication syndrome exhibit late-onset obesity and altered lipid metabolism.

  Rui Kishimoto, Kota Tamada(equally contributed), Xiaoxi Liu, Hiroko Okubo, Satoko Ise, Hisashi Ohta, Sandra Ruf, Jin Nakatani, Nobuoki Kohno, François Spitz, Toru Takumi

  Lead, Aug. 2015, Human molecular genetics, 24(16) (16), 4559 - 72, English, International magazine, Co-authored internationally

  [Refereed]

  Scientific journal


• ゲノム工学的手法を用いた自閉症モデルマウスの新奇性および低頻度性に対する反応

  岡田 佳奈, 武田 梢, 氏田 麻美, 崎本 裕也, 玉田 紘太, 内匠 透, 坂田 省吾

  日本動物心理学会, Jan. 2013, 動物心理学研究, 62(2) (2), 203 - 203, Japanese


• The period of the somite segmentation clock is sensitive to Notch activity.

  Woong Kim, Takaaki Matsui, Masataka Yamao, Makoto Ishibashi, Kota Tamada, Toru Takumi, Kenji Kohno, Shigeyuki Oba, Shin Ishii, Yuichi Sakumura, Yasumasa Bessho

  Sep. 2011, Molecular biology of the cell, 22(18) (18), 3541 - 9, English, International magazine

  [Refereed]

  Scientific journal


• ヒト染色体15q11-13重複モデルマウスにおける興奮・抑制性神経の形態学的解析

  中井 信裕, 渡辺 康仁, 都甲 めぐみ, 廣木 遥, 三嶋 亮, 笹西 美和子, 高橋 哲也, 松本 昌泰, 玉田 紘太, 内匠 透

  (一社)日本解剖学会, Mar. 2011, 解剖学雑誌, 86(1) (1), 18 - 18, Japanese


• ヒト型マウスモデルによる自閉症の病態解明と新規治療薬開発の基盤研究

  内匠 透, 玉田 紘太, 友永 省三, 畠中 史幸, 中井 信裕

  (公財)先進医薬研究振興財団, Mar. 2011, 精神薬療研究年報, (43) (43), 53 - 54, Japanese


• Decreased exploratory activity in a mouse model of 15q duplication syndrome; implications for disturbance of serotonin signaling.

  Kota Tamada, Shozo Tomonaga, Fumiyuki Hatanaka, Nobuhiro Nakai, Keizo Takao, Tsuyoshi Miyakawa, Jin Nakatani, Toru Takumi

  Lead, Dec. 2010, PloS one, 5(12) (12), e15126, English, International magazine

  [Refereed]

  Scientific journal


• 染色体工学による自閉症モデルマウスを用いた病態解明及びセロトニン系薬剤の関連研究

  内匠 透, 玉田 紘太, 畠中 史幸, 渡辺 康仁, 中井 信裕, 大塚 晋

  (公財)先進医薬研究振興財団, Mar. 2010, 精神薬療研究年報, (42) (42), 53 - 54, Japanese


• Autonomous regulation of osteosarcoma cell invasiveness by Wnt5a/Ror2 signaling

  M. Enomoto, S. Hayakawa, S. Itsukushima, D. Y. Ren, M. Matsuo, K. Tamada, C. Oneyama, M. Okada, T. Takumi, M. Nishita, Y. Minami

  Sep. 2009, ONCOGENE, 28(36) (36), 3197 - 3208, English

  [Refereed]

  Scientific journal


• Abnormal behavior in a chromosome-engineered mouse model for human 15q11-13 duplication seen in autism.

  Jin Nakatani, Kota Tamada(equally contributed), Fumiyuki Hatanaka, Satoko Ise, Hisashi Ohta, Kiyoshi Inoue, Shozo Tomonaga, Yasuhito Watanabe, Yeun Jun Chung, Ruby Banerjee, Kazuya Iwamoto, Tadafumi Kato, Makoto Okazawa, Kenta Yamauchi, Koichi Tanda, Keizo Takao, Tsuyoshi Miyakawa, Allan Bradley, Toru Takumi

  Lead, Jun. 2009, Cell, 137(7) (7), 1235 - 46, English, International magazine, Co-authored internationally

  [Refereed]

  Scientific journal

• 疾患モデル動物を用いた精神医学研究の展望

  戸谷豪志, 玉田紘太, 三澤日出巳, 内匠透

  科学評論社, 01 Mar. 2017, 精神科, 30(3) (3), 221 - 266, Japanese

  [Invited]

  Introduction scientific journal


• Chronobiology of psychiatric disorders

  戸谷 豪志, 福本 景太, 玉田 紘太, 三澤 日出巳, 内匠 遥

  金原一郎記念医学医療振興財団 ; 1949-, Nov. 2016, 生体の科学, 67(6) (6), 584 - 588, Japanese


• 自閉症研究の最新事情 (脳疾患の科学)

  福田 邦宏, 福本 景太, 玉田 紘太, 内匠 透

  東京化学同人, May 2016, 現代化学 = Chemistry today, (542) (542), 35 - 38, Japanese


• Serotonin disturbance in mouse models of autism spectrum disorders

  Kota Tamada, Toru Takumi

  Lead, Springer New York, 22 Jan. 2015, Organism Models of Autism Spectrum Disorders, 100, 239 - 262, English

  Book review


• INTEGRATIVE ANALYSIS ON NEUROPHARMACOLOGICAL EFFECTS OF HONEY

  M. Akanmu, F. Hatanaka, K. Tamada, T. Takumi

  Jul. 2014, BASIC & CLINICAL PHARMACOLOGY & TOXICOLOGY, 115, 129 - 129, English

  Summary international conference


• A humanized mouse model of autism

  TAMADA Kota, NAKAI Nobuhiro, TAKUMI Toru

  Lead, 日本生化学会, 25 Sep. 2011, 生化學, 83(9) (9), 841 - 845, Japanese, Domestic magazine


• Analysis of chromosome engineered mouse model of 15q duplication

  Kota Tamada, Shozo Tomonaga, Fumiyuki Hatanaka, Nobuhiro Nakai, Toru Takumi

  Lead, 2011, NEUROSCIENCE RESEARCH, 71, E75 - E76, English

  Summary international conference

• Elucidation of the Molecular Mechanism by which the PERIOD2 (PER2) P988L Mutation Causes Advanced Sleep Phase Syndrome

  Toshihiko Shirafuji, Kota Tamada, Marina Yamamoto, Nobuyuki Kurosawa, Hiroyuki Takeda, Shigeki Higashiyama, Toru Takumi

  APPW2025, Mar. 2025, English

  Oral presentation


• プロテオーム解析によるシナプス成熟の理解と主要シナプス後分子の同定

  貝塚 剛志, 鈴木 健裕, 岸 憲幸, 廣内 大成, 實吉 岳郎, 玉田 紘太, 白藤 俊彦, Manfred, W. Kilimann, 上山 健彦, 渡辺 雅彦, 下郡 智美, 岡野 栄之, Mark O. Collins、Seth, G.N. Gran, 林 康紀, 堂前 直, 内匠 透

  NEURO2024, Jul. 2024

  Public symposium


• Genetic dissection identifies Necdin as a driver gene in 15q duplication syndrome

  Kota Tamada, Toru Takumi

  The 46th Annual Meeting of the Japan Neuroscience Society, Aug. 2023, English

  [Invited]

  Public symposium


• 自閉症モデルマウスの脳機能解明に向けた無麻酔fMRI法の開発

  釣木澤 朋和, 玉田 絋太, 内匠 透

  第49回日本脳科学会, Dec. 2022

  Oral presentation


• Prucalopride restores the delayed gastrointestinal transit in preclinical mouse model of 15q duplication syndrome

  Gayathri Balasuriya, Kota Tamada, Jun Nomura, Toru Takumi

  Neuro2022, Jun. 2022

  Oral presentation


• Genetic dissection identifies Necdin as a driver gene in 15q duplication syndrome

  Kota Tamada, Keita Fukumoto, Tsuyoshi Toya, Nobuhiro Nakai, Janak R Awasthi, Shinji Tanaka, Shigeo Okabe, Francois Spitz, Toru Takumi

  Seattle-Kobe Virtual Symposium, The 5th UW-KU International Joint Symposium, Sep. 2021

  [Invited]

  Nominated symposium


• Genetic dissection identifies Necdin as a driver gene in 15q duplication syndrome

  Kota Tamada, Keita Fukumoto, Tsuyoshi Toya, Nobuhiro Nakai, Janak Awasthi, Shinji Tanaka, Shigeo Okabe, Francois Spitz, Toru Takumi

  The 44th Annual Meeting of the Japan Neuroscience Society, Jul. 2021, English

  Oral presentation


• Genetic dissection identifies Necdin as a driver gene in 15q duplication syndrome

  Kota Tamada

  The 3rd Kobe U = RIKEN BDR Joint Symposium, Mar. 2021

  Poster presentation


• Genetic dissection identifies Necdin as a driver gene in 15q11-q13 duplication syndrome

  Kota Tamada, Keita Fukumoto, Tsuyoshi Toya, Nobuhiro Nakai, Janak Awasthi, Shinji Tanaka, Shigeo Okabe, Spitz Francois, Toru Takumi

  The 43th Annual Meeting of the Japan Neuroscience Society, Aug. 2020, English

  Oral presentation


• Awake functional MRI detects the neural circuit dysfunction in 15 dup autism model mouse

  Tomokazu Tsurugizawa, Kota Tamada, Toru Takumi

  The 12th FENS, 11-15 July, 2020, Glasgow, UK, Jul. 2020

  Oral presentation


• 自閉症責任領域ヒト染色体15q11-q13における原因遺伝子の解析

  玉田 紘太, 福本 景太, 戸谷 豪志, Ruf Sandra, Spitz Francois, 内匠 透

  第42回 日本分子生物学会, Dec. 2019

  Others


• Awake mouse functional MRI reveals the abnormal neural circuit in autism model mouse

  Tomokazu Tsurugizawa, Kota Tamada, Akihiko Kitamura, Toru Takumi

  NEURO2019, Jul. 2019

  Oral presentation


• Identification of the critical gene in 15q11-q13 duplication syndrome

  Kota Tamada, Keita Fukumoto, Tsuyoshi Toya, Nobuhiro Nakai, Janak Awasthi, Sandra Ruf, Francois Spitz, Toru Takumi

  Neuro2019, Jul. 2019, English, International conference, Co-authored internationally

  Poster presentation


• Systematic analysis of brain pH and lactate levels in animal models: relationships and implications for behavioral outcomes

  Hideo Hagihara, Hirotaka Shoji, Takao Kohno, Atsuko Hayata, Kota Tamada, Kei Hori, Tetsuya Tatsukawa, Mihiro Shibutani, Shuji Wakatsuki, Yoko Hagino, Takaoki Kasahara, Tadahiro Numakawa, Hikari Ohtabi, Ikuo Nobuhisa, Yoshio Hoshiba, Haruko Nakamura, Shota Katori, Kyosuke Yamanishi, Yoshihiro Takamiya, Mika Tanaka, Ipek Yalcin, Masayuki Matsushita, Mitsuharu Hattori, Hitoshi Hashimoto, Toru Takumi, Mikio Hoshino, Katsuhiko Tabuchi, Kazuhiro Yamakawa, Izuho Hatada, Kazutaka Ikeda, Tadafumi Kato, Hiroshi Kunugi, Atsushi Toyoda, Tetsuya Taga, Akiko Hayashi-Takagi, Yoshio Goshima, Takuji Iwasato, Shigeo Okabe, Herbert Y Meltzer, Tsuyoshi Miyakawa

  The 21st Annual Meeting of the International Behavioural and Neural Genetics Society, Genes, Brain and Behavior 2019, May 10-14, 2019, Edinburgh, Scotland,, May 2019

  Oral presentation


• In vivo screening of maternally imprinted genes in human chromosome 15q11-13

  Kota Tamada, Keita Fukumoto, Tsuyoshi Toya, Nobuhiro Nakai, Janak Awasthi, Sandra Ruf, Francois Spitz, Tomokazu Tsurugizawa, Toru Takumi

  RIKEN Epigenetics in Wako, Feb. 2019, English, International conference, Co-authored internationally

  Poster presentation


• 自閉症責任領域15q11-q13モデルマウスにおける原因遺伝子の探索

  玉田 紘太, 福本 景太, 戸谷 豪志, Ruf Sandra, Spitz Francois, 内匠 透

  次世代脳プロジェクト2018年度冬のシンポジウム, Dec. 2018, Japanese, Domestic conference, Co-authored internationally

  Oral presentation


• 転写抑制因子Id2は前腸転写因子Irk5の発言抑制を介して腸のアイデンティテイーを決定する

  森 健太郎, 中村 ハルミ, 黒岡 尚徳, 宮地 均, 玉田 紘太, 菅井 学, 松井 真, 内匠 透, 横田 義史

  第41回日本分子生物学会年会, Nov. 2018

  Oral presentation


• Necdin promotes formation of dendritic spines in ASD model mice for 15q syndrome

  Tsuyoshi Toya, Keita Fukumoto, Nobuhiro Nakai, Shinji Tanaka, Shigeo Okabe, Peter Scheiffele, Hidemi Misawa, Kota Tamada, Toru Takumi

  次世代脳プロジェクト冬のシンポジウム 2017, Dec. 2017

  Oral presentation


• 自閉症責任領域15q11-q13モデルマウスにおける原因遺伝子の探索

  玉田 紘太, 福本 景太, 戸谷 豪志, Ruf Sandra, Spitz Francois, 内匠 透

  ConBio 2017, Dec. 2017, Japanese, Co-authored internationally


• Awake mouse functional MRI for the detection of the abnormal neural circuit in autism model mouse

  Tomokazu Tsurugizawa, Kota Tamada, Akihiko Kitamura, Nobukazu Ono, S. Karakawa, Y. Kodama, Toru Takumi

  Neuroscience 2017 (Washington DC, USA), Nov. 2017

  Public symposium


• Serotonin intervention alleviates cortical response to sensory stimuli and social behavior in human 15q duplication model mice

  Nobuhiro Nakai, Masatoshi Nagano, Fumihito Saitow, Yasuhito Watanabe, Yoshinobu Kawamura, Hiroshi Mizuma, Hirotaka Onoue, Kota Tamada, Hiromu Monai, Hajime Hirase, Taisuke Miyazaki, Masahiko Watanabe, Shigeo Okabe, Masanobu Kano, Kouichi Hashimoto, Hidenori Suzuki, Toru Takumi

  Neuroscience 2017, Nov. 2017

  Oral presentation


• Serotonin rebalances cortical tuning and behavior linked to autism symptoms in 15q11-13 CNV

  Nobuhiro Nakai, Masatoshi Nagano, Fumihito Saitow, Yasuhito Watanabe, Yoshinobu Kawamura, Hiroshi Mizuma, Hirotaka Onoue, Kota Tamada, Hiromu Monai, Hajime Hirase, Taisuke Miyazaki, Masahiko Watanabe, Shigeo Okabe, Masanobu Kano, Kouichi Hashimoto, Hidenori Suzuki, Toru Takumi

  第40回日本神経科学大会, Jul. 2017

  Oral presentation


• Necdin regulates spine dynamics in 15q duplicated model mice

  Tsuyoshi Toya, Keita Fukumoto, Nobuhiro Nakai, Shinji Tanaka, Shigeo Okabe, Peter Scheiffele, Hidemi Misawa, Kota Tamada, Toru Takumi

  第40回日本神経科学大会, Jul. 2017

  Oral presentation


• Functional neuroimaging for translational research of neuropsychiatric disorders; from human to mouse

  Tomokazu Tsurugizawa, Kota Tamada, Nobukazu Ono, Akihiko Kitamura, Toru Takumi

  第４０回日本神経科学大会, Jul. 2017

  Public symposium


• Necdin regulates spine dynamics in 15q duplication mode mice

  戸谷 豪, 福本 景太, 玉田 紘太, 田中 慎二, 三澤 日出巳, 岡部 繁男, 内匠 透

  第１２２回日本解剖学会全国学術集会, Mar. 2017

  Public symposium


• Necdin facilitates spine regulation in 15q duplication model mice

  Tsuyoshi Toya, Keita Fukumoto, Kota Tamada, Shinji Tanaka, Hidemi Misawa, Shigeo Okabe, Toru Takumi

  RIKEN 2017 Joint Retreat, Feb. 2017

  Oral presentation


• Dosage-dependent cognitive dysfunctions in a genetic mouse model of 2q13 (Nphp1) duplication

  Keiko Kishimoto, Jun Nomura, Kota Tamada, Thomas Bourgeron, Mereno Du Luca Daniel, Toru Takumi

  第39回日本神経科学大会, Jul. 2016

  Oral presentation


• Wnt5a-Ror2シグナルは繊毛タンパク質IFT29の発現誘導を介してがん細胞の浸潤を制御する

  西田 満, 西尾 忠, 紙崎 孝基, 王 志超, 榎本 真宏, 玉田 紘太, 内匠 透, Victor W Hsu, Gregory J. Pazour, 南 康博

  BMB2015第３８回日本分子生物学会、第８８回日本生化学会合同大会, Dec. 2015

  Oral presentation


• Perseveration behavior and impaired detection in sensory information processing with the social and non-social situation of the model mice for autism

  Kana Okada, Kota Tamada, Asami Ujita, Jin Nakatani, Toru Takumi, Shogo Sakata

  日本動物心理学会第74回大会, Jul. 2014

  Oral presentation


• Integrative analysis on neuropharmacological effects of honey

  Moses A Akanmu, Fumiyuki Hatanaka, Kota Tamada, Toru Takumi

  The 17th World Congress of Basic and Clinical Pharmacology, 13-18 July, 2014, Cape Town, South Africa, Jul. 2014

  Oral presentation


• ヒト染色体15q11-13相同領域重複マウスにおける肥満メカニズムの解析

  岸本 瑠衣, 玉田 紘太, 中西 修平, 河野 修興, 内匠 透

  第36回日本分子生物学会年会, Dec. 2013

  Oral presentation


• 概日リズムとうつ病の調節機構としてのPERIOD2-glycogen synthase kinase 3経路

  山脇 洋輔, 高野 敦子, 仲西 萌絵, 玉田 紘太, 畠中 史幸, 内匠 透

  Neuro 2013, Jun. 2013

  Oral presentation


• 転写抑制因子Id2による消化管上皮細胞の運命決定機構

  森 健太郎, 中村 ハルミ, 宮地 均, 玉田 紘太, Chi-Chung Hui, 内匠 透, 横田 義史

  Dec. 2012

  Oral presentation


• ゲノム工学的手法を用いた自閉症モデルマウスの新奇性および低頻度性に対する反応

  岡田 佳奈, 武田 梢, 氏田 麻美, 崎本 裕也, 玉田 紘太, 内匠 透, 坂田 省吾

  第72回日本動物心理学会大会, May 2012

  Oral presentation


• ヒト染色体１５q１１−１３重複モデルマウスにおけるE/I比の解析

  福本 景太, 渡辺 康仁, 中井 信裕, 五林 優子, 玉田 紘太, 高橋 哲也, 松本 昌泰, 樋田 一徳, 内匠 透

  第117回日本解剖学会全国学術集会, Mar. 2012

  Oral presentation


• 転写抑制因子Id2による消化管上皮細胞の運命決定機構

  森 健太郎, 中村 ハルミ, 宮地 均, 玉田 紘太, Chi-Chung Hui, 内匠 透, 横田 義史

  第34回日本分子生物学会年会, Dec. 2011

  Oral presentation


• Analysis of chromosome engineered mouse model of 15q duplication syndrome

  Kota Tamada, Shozo Tomonaga, Fumiyuki Hatanaka, Nobuhiro Nakai, Jin Nakatani, Toru Takumi

  The 32nd Naito Conference, Oct. 2011, English, International conference

  Poster presentation


• Analysis of chromosome engineered mouse model of 15q duplication.

  Kota Tamada, Shozo Tomonaga, Fumiyuki Hatanaka, Nobihiro Nakai, Toru Takumi

  The 34th Annual Meeting of the Japan Neuroscience Society, Sep. 2011, English, International conference

  Oral presentation


• 自閉症責任領域であるヒト染色体15q11-13重複モデルマウスの解析

  玉田 紘太, 友永 省三, 畠中 史幸, 中井 信裕, 中谷 仁, 内匠 透

  包括脳 夏のワークショップ, Aug. 2011, English, Domestic conference

  Poster presentation


• 転写抑制因子Id2による消化管上皮細胞の運命決定機構

  森 健太郎, 中村 ハルミ, 玉田 紘太, 内匠 透, 横田 義史

  第44回日本発生生物学会大会, May 2011

  Oral presentation


• ヒト染色体15q11-13相同領域重複マウスの解析

  玉田 紘太, 中谷 仁, 友永 省三, 畠中 史幸, 中井 信裕, 内匠 透

  第52回日本生化学会中国・四国支部例会, May 2011, Japanese, 2011Seikagaku.doc, No password, Domestic conference

  Oral presentation

  添付ファイルのURL


• インプリンティング領域であるヒト染色体15q11-13相同領域重複マウスの解析

  玉田 紘太, 中谷 仁, 畠中 史幸, 中井 信裕, 大塚 晋, 内匠 透

  第33回日本分子生物学会年会・第83回日本生化学会大会 合同大会, Dec. 2010, Japanese, BMB2010.doc, No password, International conference

  Public symposium

  添付ファイルのURL


• ヒト染色体15q11-13重複モデルマウスにおける興奮・抑制性神経の形態学的解析

  中井 信裕, 渡辺 康仁, 都甲 めぐみ, 廣木 遥, 三嶋 亮, 笹西 美和子, 高橋 哲也, 松本 昌泰, 玉田 紘太, 内匠 透

  第65回日本解剖学会中国・四国支部学術集会, Oct. 2010

  Oral presentation


• 染色体工学を用いて作製したヒト染色体15q11-13相同領域重複マウスの解析

  玉田 紘太, 中谷 仁, 畠中 史幸, 伊瀬 聖子, 太田 尚, 井上 浄, 友永 省三, 渡辺 康仁, 岩本 和也, 加藤 忠史, 高雄 啓三, 宮川 剛, Allan Bradley, 内匠 透

  第82回日本生化学会大会, Oct. 2009, Japanese, 2009Seikagaku.doc, No password, Domestic conference, Co-authored internationally

  Oral presentation

  添付ファイルのURL


• Wnt5a/Ror2経路はMMP−１３を介して骨肉腫細胞の invadopodia形成と浸潤を制御する

  榎本 真宏, 早川 沙織, 任 大勇, 玉田 紘太, 内匠 透, 西田 満, 南 康博

  Dec. 2008

  Oral presentation


• 染色体工学を用いて作製したヒト染色体15q11-13重複マウスの解析

  中谷 仁, 玉田 紘太, 畠中 史幸, 井上 浄, 伊瀬 聖子, 太田 尚, 岩本 和也, 加藤 忠史, 短田 浩一, 宮川 剛, Allan Bradley, 内匠 透

  第31回日本分子生物学会年会・第81回日本生化学会大会 合同大会, Dec. 2008, Japanese, BMB2008.doc, No password, International conference, Co-authored internationally

  Oral presentation

  添付ファイルのURL


• Analysis of the chromosome-engineered mouse model for autism

  Jin Nakatani, Kota Tamada, Fumiyuki Hatanaka, Kiyoshi Inouse, Satoko Ise, Hisashi Ohta, Koichi Tanda, Tsuyoshi Miyakawa, Allan Bradley, Toru Takumi

  BMB2007, Dec. 2007, English, BMB2007.doc, Published, No password, International conference, Co-authored internationally

  Public symposium

  添付ファイルのURL

• The Japan Neuroscience Society


• The Japanese Biochemical Society


• The Molecular Biology Society of Japan


• 日本生理学会

• Analysis of the dendritic spine abnormality in autism spectrum disorder

  Kota Tamada

  Takeda Science Foundation, 医学系研究助成, 神戸大学, Aug. 2023 - Aug. 2026, Principal investigator


• Analysis of dendritic spine turnover as an endophenotype in ASD

  玉田 紘太

  Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research (C), Kobe University, 01 Apr. 2023 - 31 Mar. 2026


• Elucidation of the molecular mechanism for dysfunction of circadian rhythm caused by maternal immune activation

  玉田 紘太, 益子 尚久

  Center for Medical Transformation, CMX若手共同研究プロジェクト, 神戸大学, Jul. 2023 - Mar. 2024, Principal investigator


• 新規自閉症関連遺伝子、NDN遺伝子の分子メカニズム解明

  玉田 紘太

  公益財団法人ひょうご科学技術協会, 令和５年度学術研究助成, Apr. 2023 - Mar. 2024, Principal investigator


• 自閉症責任領域である15q11-q13におけるNDN遺伝子の機能解明

  玉田 紘太

  公益財団法人 かなえ医薬振興財団, 2021年度(第50回)かなえ医薬振興財団助成金, Feb. 2022 - Mar. 2023, Principal investigator


• ヒト染色体15q11-q13自閉症領域の責任遺伝子同定と病態メカニズムの解明

  玉田 紘太

  Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C), Grant-in-Aid for Scientific Research (C), Kobe University, Apr. 2020 - Mar. 2023, Principal investigator

  ヒト染色体15q11-13の重複は自閉症において高頻度に認められる染色体異常である。本研究代表者らは本領域を重複させた自閉症モデルマウス(15q dup)の作製し、自閉症様の行動学的異常、縫線核におけるセロトニン神経の活動低下、幼少期におけるシナプス代謝亢進など、種々の特徴的な異常を見出してきた。 本研究目的は、自閉症様行動異常、またはシナプス異常に対して、15q11-13領域におけるどの遺伝子が重要であるかを同定すること、またその分子メカニズムを明らか にすることである。本年度は①標的遺伝子(Ndn)の同定を報告する論文投稿、②昨年から引き続き、下流同定のためのFIN seqの立ち上げ、③FMRPとNDNの関係性の解析、④1細胞レベル、またはNdn過剰発現神経細胞における超解像顕微鏡を用いたスパインの詳細な解析、の4つの事項について行った。①：査読者より指摘された箇所について追加実験を行い、Ndn遺伝子が15q dupマウスの異常表現型において、重要であることを更に強く証明した。②：Ndn遺伝子のスパイン形成における機能は核内におけるNdnが重要と考えられる。そこで次に、Frozen Immunolabled Nuclei Sequencing (FIN seq, Amamoto et al.,2019)を用いてNdnが導入された細胞を抽出、mRNAの発現解析を行い、Ndnの直接的な下流因子を同定する。昨年に引き続き、本方法のセットアップを行い、ほぼ完了した。③：これまでに明らかでなかった脆弱X症候群の原因遺伝子、FMRPがNDNと分子的な関与がある可能性を見出し、現在その関係性について解析している。④：1細胞レベルでのNdn過剰発現神経細胞におけるスパインの解析を行うために、Supernovaシステム(Luo et al., 2016)を代表者の所属する研究室にて立ち上げた。また、超解像顕微鏡による、より詳細なスパインの解析を行うために、そのサンプルを準備した。


• マウス覚醒下fMRIを用いたうつ脆弱性・抵抗性と脳機能との相関解析

  玉田 紘太

  Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area), Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area), Apr. 2019 - Mar. 2021, Principal investigator

  うつ病は遺伝的要因のみならず、環境・経験によって引き起こされる部分が大きいと考えられる。そのため、その病態解明および原因解明の研究には環境変化・経験前後の比較研究が重要と考えられる。ヒトは遺伝学的・環境要因を統一することが難しいため、切り分けができない一方で、モデル生物、例えばマウスのような齧歯類では遺伝的背景が統一されているため、環境・経験による要因を解析することが可能となる。しかし、これまでの研究手法ではそのストレスが加わる前後、および途中の解析、すなわち動物を生かしながらストレスの影響を検討・解析する、ということは限られた手法しか存在しない。また、その手法自体にも現存する問題点があり、特に細胞でもなく、個体レベルでもない中間的視点の定量的解析方法が不足していると考えられる。そのため、脳機能の変化を同一個体で追うことは現時点では難しい。ストレスによる“脳機能の変化”こそ、うつ病の事前リスク、および発症にいたる前の個別の閾値を調べることが可能になるのではないかと仮説を立てた。 本研究ではマウスの覚醒下におけるfunctional magnetic resonance imaging (fMRI)を用いて、ストレスが脳内機能的連絡にどのような変化をもたらすかをストレス経験前、途中、後の３点の時間軸にて明らかにすることを目的とする。また、この機能的連絡と行動試験結果の間の相関関係を調べ、個体毎のストレス脆弱性/耐性についての因果関係に迫る。 本年度はsocial defeat stress(SDS, 社会的敗北ストレス)を用いて、ストレス付与前、５日間のストレス後、１０日間のストレスを与え、それぞれに対応した、fMRIのデータ取得を行った。次年度、これらのデータ解析を行い、結果の検討を行うものとする。


• Expression and functional analysis of the imprinting genes located in 15q11-13

  Tamada Kota

  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), Institute of Physical and Chemical Research, Apr. 2016 - Mar. 2019, Principal investigator

  The cytogenetic aberration of human chromosome 15q11-q13 causes neurodevelopmental disorders including autism, Prader-Willi (PWS) and Angelman syndrome (AS). Duplication of this region, called 15q11-13 duplication syndrome, is the most frequently found in cytogenetic abnormality in autism. Thus, precise expression of the genes in this region is critical for normal brain development. Previously, we modeled this chromosome duplication in mice and found paternally inherited duplication (patDp/+) causes abnormal social behaviors and serotonin imbalance. In this study, we identified Ndn genes is critical not only for autistic like behaviors but synaptic development or cortical excitatory/inhibitory balance.


• Analysis of self-other recognition in mice model for autism

  TAMADA Kota

  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), Apr. 2012 - Mar. 2015, Principal investigator

  Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by less social interaction / communication or repetitive behaviors. Despite recent intensive researches, its molecular mechanism remains largely unclear. Recently, our research group succeeded to generate mice model (patDp/+) for ASD that have duplicated chromosome 7B to C region, corresponding to human chromosome 15q11-13 which is one of the responsible locus for ASD. In this study, we addressed the self-other recognition mechanism by using this model and tried to find causative molecule in the brain. Compared to WT mice, patDp/+ mice showed altered brain activity stimulated by the odor of other mice or self. PatDp/+ mice had decreased levels of a specific amino acid in the brain both in adult and postnatal developmental period. These results suggest that the imbalance of amino acids in brain might be a critical role in the social abnormalities found in ASD.