研究職歴 2014- , 信州大学学術研究院医学系 分子細胞生理学教室 教授 2012-2014 , 信州大学医学部 分子細胞生理学講座 教授 2009-2012 , 生理学研究所 准教授 2008-2009 , Stanford University School of Medicine Life Science Research Associate 2007-2008 , UT Southwestern Medical Center Instructor 2005-2007 , UT Southwestern Medical Center Assistant Instructor 2001-2005 , Postdoctoral fellow UT Southwestern Medical Center 1999-2001 , Postdoctoral fellow Howard Hughes Medical Institute
研究活動業績
研究業績（著書・ 発表論文等）
書籍等出版物 Analysis of Neuroligin-3 R451C knock-in mice as models for autistic savant, 日本生物学的精神医学会誌 23 4, 281-286 2012
論文 An epilepsy-associated mutation of salt-inducible kinase 1 increases the susceptibility to epileptic seizures and interferes with adrenocorticotropic hormone therapy for infantile spasms in mice. Int. J. Mol. Sci., in press. 2022(Jul.) Author:Pang B; Mori T; Badawi M; Zhou M; Guo Q; Kouyama-Suzuki E; Yanagawa T; Yoshinori Shirai Y; Tabuchi K
IQSEC3 Deletion Impairs Fear Memory Through Upregulation of Ribosomal S6K1 Signaling in the Hippocampus. Biological psychiatry,91(9):821-831 2022(May 01) Author:Dongwook Kim; Hyeji Jung; Yoshinori Shirai; Hyeonho Kim; Jinhu Kim; Dongseok Lim; Takuma Mori; Hyojeong Lee; Dongseok Park; Hee Young Kim; Qi Guo; Bo Pang; Wen Qiu; Xueshan Cao; Emi Kouyama-Suzuki; Takeshi Uemura; Enas Kasem; Yu Fu; Seungjoon Kim; Akinori Tokunaga; Takahiro Yoshizawa; Tatsuo Suzuki; Hiroyuki Sakagami; Kea Joo Lee; Jaewon Ko; Katsuhiko Tabuchi*; Ji Won Um* (*Tabuchi and Um are corresponding authors.) Abstract:BACKGROUND: IQSEC3, a gephyrin-binding GABAergic (gamma-aminobutyric acidergic) synapse-specific guanine nucleotide exchange factor, was recently reported to regulate activity-dependent GABAergic synapse maturation, but the underlying signaling mechanisms remain incompletely understood. METHODS: We generated mice with conditional knockout (cKO) of Iqsec3 to examine whether altered synaptic inhibition influences hippocampus-dependent fear memory formation. In addition, electrophysiological recordings, immunohistochemistry, and behavioral assays were used to address our question. RESULTS: We found that Iqsec3-cKO induces a specific reduction in GABAergic synapse density, GABAergic synaptic transmission, and maintenance of long-term potentiation in the hippocampal CA1 region. In addition, Iqsec3-cKO mice exhibited impaired fear memory formation. Strikingly, Iqsec3-cKO caused abnormally enhanced activation of ribosomal P70-S6K1-mediated signaling in the hippocampus but not in the cortex. Furthermore, inhibiting upregulated S6K1 signaling by expressing dominant-negative S6K1 in the hippocampal CA1 of Iqsec3-cKO mice completely rescued impaired fear learning and inhibitory synapse density but not deficits in long-term potentiation maintenance. Finally, upregulated S6K1 signaling was rescued by IQSEC3 wild-type, but not by an ARF-GEF (adenosine diphosphate ribosylation factor-guanine nucleotide exchange factor) inactive IQSEC3 mutant. CONCLUSIONS: Our results suggest that IQSEC3-mediated balanced synaptic inhibition in hippocampal CA1 is critical for the proper formation of hippocampus-dependent fear memory.
Neurexins play a crucial role in cerebellar granule cell survival by organizing autocrine machinery for neurotrophins. Cell reports,39(1):110624-110624 2022(Apr. 05) Author:Takeshi Uemura; Emi Suzuki-Kouyama; Shiori Kawase; Taiga Kurihara; Misato Yasumura; Tomoyuki Yoshida; Shuya Fukai; Maya Yamazaki; Peng Fei; Manabu Abe; Masahiko Watanabe; Kenji Sakimura; Masayoshi Mishina; Katsuhiko Tabuchi Abstract:Neurexins (NRXNs) are key presynaptic cell adhesion molecules that regulate synapse formation and function via trans-synaptic interaction with postsynaptic ligands. Here, we generate cerebellar granule cell (CGC)-specific Nrxn triple-knockout (TKO) mice for complete deletion of all NRXNs. Unexpectedly, most CGCs die in these mice, and this requirement for NRXNs for cell survival is reproduced in cultured CGCs. The axons of cultured Nrxn TKO CGCs that are not in contact with a postsynaptic structure show defects in the formation of presynaptic protein clusters and in action-potential-induced Ca2+ influxes. These cells also show impaired secretion of depolarization-induced, fluorescence-tagged brain-derived neurotrophic factor (BDNF) from their axons, and the cell-survival defect is rescued by the application of BDNF. These results suggest that CGC survival is maintained by autocrine neurotrophic factors and that NRXNs organize the presynaptic protein clusters and the autocrine neurotrophic-factor secretory machinery independent of contact with postsynaptic ligands.
Nasal molding prevents relapse of nasal deformity after primary rhinoplasty in patients with unilateral complete cleft lip: An outcomes‐based comparative study of palatal plate alone versus nasoalveolar molding Clinical and Experimental Dental Research,8(1):197-208 2022(Feb.) Author:Yukiko Aihara; Toru Yanagawa; Masahiro Sasaki; Kaoru Sasaki; Yoichiro Shibuya; Koji Adachi; Shinji Togashi; Shohei Takaoka; Katsuhiko Tabuchi; Hiroki Bukawa; Mitsuru Sekido Abstract:OBJECTIVES: In recent years, many studies have reported that the presurgical nasoalveolar molding method improves the nose morphology; however, the reason for its effectiveness after surgery has never been understood. We evaluated the effect of nasoalveolar molding by comparing it with a passive orthopedic method without a nasal stent and focusing on the nostril morphology after primary cheiloplasty using various measurement methods. We then analyzed the essential factors. MATERIALS AND METHODS: The patients involved were 31 infants with unilateral complete cleft lip and palate treated with primary cheiloplasty at the University of Tsukuba Hospital from 2004 to 2011. Of the 31 infants, 16 received nasoalveolar molding treatment and 15 received passive orthopedic treatment as controls. Photographic facial measurements were performed for all patients immediately and 7 months after primary cheiloplasty. The esthetics of the nostrils were assessed according to the left-right nostril symmetry, as measured by the Hausdorff distance, area ratio, perimeter ratio, and aspect a/u (the aspect ratio of the affected side)/(the aspect ratio of the unaffected side) ratio. In addition, the inclination of the nasal ridge was assessed using anthropometric measurements (Grc-Grn∠midline and midline∠columellar axis). RESULTS: The area ratio, perimeter ratio, and Grc-Grn∠midline were significantly greater in the nasoalveolar molding group immediately after surgery (p = 0.00062, 0.016, and 0.048, respectively) than in the control group. However, the Hausdorff distance and aspect a/u ratio were more favorable (p = 0.0018 and 0.0039, respectively) in the nasoalveolar molding group after 7 months. CONCLUSIONS: The results of our study suggested that using nasoalveolar molding as a presurgical orthopedic treatment could improve the shape of the nasal cartilage with surgeon's corrections.
IQSEC2 Deficiency Results in Abnormal Social Behaviors Relevant to Autism by Affecting Functions of Neural Circuits in the Medial Prefrontal Cortex. Cells,10(10) 2021(Oct. 12) Author:Anuradha Mehta; Yoshinori Shirai; Emi Kouyama-Suzuki; Mengyun Zhou; Takahiro Yoshizawa; Toru Yanagawa; Takuma Mori; Katsuhiko Tabuchi Abstract:IQSEC2 is a guanine nucleotide exchange factor (GEF) for ADP-ribosylation factor 6 (Arf6), of which protein is exclusively localized to the postsynaptic density of the excitatory synapse. Human genome studies have revealed that the IQSEC2 gene is associated with X-linked neurodevelopmental disorders, such as intellectual disability (ID), epilepsy, and autism. In this study, we examined the behavior and synapse function in IQSEC2 knockout (KO) mice that we generated using CRIPSR/Cas9-mediated genome editing to solve the relevance between IQSEC2 deficiency and the pathophysiology of neurodevelopmental disorders. IQSEC2 KO mice exhibited autistic behaviors, such as overgrooming and social deficits. We identified that up-regulation of c-Fos expression in the medial prefrontal cortex (mPFC) induced by social stimulation was significantly attenuated in IQSEC2 KO mice. Whole cell electrophysiological recording identified that synaptic transmissions mediated by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), N-methyl-D-aspartate receptor (NMDAR), and γ-aminobutyric acid receptor (GABAR) were significantly decreased in pyramidal neurons in layer 5 of the mPFC in IQSEC2 KO mice. Reexpression of IQSEC2 isoform 1 in the mPFC of IQSEC2 KO mice using adeno-associated virus (AAV) rescued both synaptic and social deficits, suggesting that impaired synaptic function in the mPFC is responsible for social deficits in IQSEC2 KO mice.
MicroRNA 142-5p promotes tumor growth in oral squamous cell carcinoma via the PI3K/AKT pathway by regulating PTEN. Heliyon,7(10):e08086-e08086 2021(Oct.) Author:Seiichiro Iizumi; Fumihiko Uchida; Hiroki Nagai; Shohei Takaoka; Satoshi Fukuzawa; Naomi Ishibashi Kanno; Kenji Yamagata; Katsuhiko Tabuchi; Toru Yanagawa; Hiroki Bukawa Abstract:MicroRNAs (miRNAs) play an important role in carcinogenesis and cancer progression. The purpose of this study was to identify miRNAs associated with carcinoma function in OSCC and to investigate the potential role of the specific miRNAs. First, a comprehensive microarray analysis was performed, and miR-142-5p was identified as a candidate miRNA involved in OSCC. miR-142-5p has been reported to show high expression levels in cancer patients and to be involved in tumor growth and metastasis. However, the expression and function of miR-142-5p in oral squamous cell carcinoma (OSCC) are not fully characterized. We evaluated miR-142-5p expression in both OSCC-derived cell lines and primary OSCC tissues and performed functional analysis of miR-142-5p in OSCC-derived cell lines using mimics and inhibitors. miR-142-5p expression was up-regulated in OSCC tissues and OSCC cell lines. Overexpression of miR-142-5p significantly promoted the proliferation and invasion of OSCC cells. Bioinformatics analysis was performed using TargetScan to predict potential target sites that match the seed region of miR-142-5p. Phosphatase and tensin homolog deleted on chromo-some 10 (PTEN) was identified as a potential target and selected for further analysis. PTEN expression levels were down-regulated and AKT expression levels were up-regulated in miR-142-5p-overexpressing cells. We have shown that miR-142-5p targets the PTEN gene and is involved in cancer progression. Our results suggest that miR-142-5p is involved in the progression of OSCC by controlling the phosphatidylinositol 3-kinase (PI3K)/AKT pathway by targeting the PTEN gene. Our findings suggest that miR-142-5p may be a new target for the treatment of OSCC.
Npas4 regulates IQSEC3 expression in hippocampal somatostatin interneurons to mediate anxiety-like behavior. Cell reports,36(3):109417-109417 2021(Jul. 20) Author:Seungjoon Kim; Dongseok Park; Jinhu Kim; Dongwook Kim; Hyeonho Kim; Takuma Mori; Hyeji Jung; Dongsu Lee; Sookyung Hong; Jongcheol Jeon; Katsuhiko Tabuchi; Eunji Cheong; Jaehoon Kim; Ji Won Um; Jaewon Ko Abstract:Activity-dependent GABAergic synapse plasticity is important for normal brain functions, but the underlying molecular mechanisms remain incompletely understood. Here, we show that Npas4 (neuronal PAS-domain protein 4) transcriptionally regulates the expression of IQSEC3, a GABAergic synapse-specific guanine nucleotide-exchange factor for ADP-ribosylation factor (ARF-GEF) that directly interacts with gephyrin. Neuronal activation by an enriched environment induces Npas4-mediated upregulation of IQSEC3 protein specifically in CA1 stratum oriens layer somatostatin (SST)-expressing GABAergic interneurons. SST+ interneuron-specific knockout (KO) of Npas4 compromises synaptic transmission in these GABAergic interneurons, increases neuronal activity in CA1 pyramidal neurons, and reduces anxiety behavior, all of which are normalized by the expression of wild-type IQSEC3, but not a dominant-negative ARF-GEF-inactive mutant, in SST+ interneurons of Npas4-KO mice. Our results suggest that IQSEC3 is a key GABAergic synapse component that is directed by Npas4 and ARF activity, specifically in SST+ interneurons, to orchestrate excitation-to-inhibition balance and control anxiety-like behavior.
Risperidone Mitigates Enhanced Excitatory Neuronal Function and Repetitive Behavior Caused by an ASD-Associated Mutation of SIK1. Frontiers in molecular neuroscience,14:706494-706494 2021(Jul. 06) Author:Moataz Badawi; Takuma Mori; Taiga Kurihara; Takahiro Yoshizawa; Katsuhiro Nohara; Emi Kouyama-Suzuki; Toru Yanagawa; Yoshinori Shirai; Katsuhiko Tabuchi Abstract:Six mutations in the salt-inducible kinase 1 (SIK1)-coding gene have been identified in patients with early infantile epileptic encephalopathy (EIEE-30) accompanied by autistic symptoms. Two of the mutations are non-sense mutations that truncate the C-terminal region of SIK1. It has been shown that the C-terminal-truncated form of SIK1 protein affects the subcellular distribution of SIK1 protein, tempting to speculate the relevance to the pathophysiology of the disorders. We generated SIK1-mutant (SIK1-MT) mice recapitulating the C-terminal-truncated mutations using CRISPR/Cas9-mediated genome editing. SIK1-MT protein was distributed in the nucleus and cytoplasm, whereas the distribution of wild-type SIK1 was restricted to the nucleus. We found the disruption of excitatory and inhibitory (E/I) synaptic balance due to an increase in excitatory synaptic transmission and enhancement of neural excitability in the pyramidal neurons in layer 5 of the medial prefrontal cortex in SIK1-MT mice. We also found the increased repetitive behavior and social behavioral deficits in SIK1-MT mice. The risperidone administration attenuated the neural excitability and excitatory synaptic transmission, but the disrupted E/I synaptic balance was unchanged, because it also reduced the inhibitory synaptic transmission. Risperidone also eliminated the repetitive behavior but not social behavioral deficits. These results indicate that risperidone has a role in decreasing neuronal excitability and excitatory synapses, ameliorating repetitive behavior in the SIK1-truncated mice.
Non-microtubule tubulin-based backbone and subordinate components of postsynaptic density lattices LIFE SCIENCE ALLIANCE,4(7) 2021(Jul.) Author:Suzuki, Tatsuo; Terada, Nobuo; Higashiyama, Shigeki; Kametani, Kiyokazu; Shirai, Yoshinori; Honda, Mamoru; Kai, Tsutomu; Li, Weidong; Tabuchi, Katsuhiko Abstract:A purification protocol was developed to identify and analyze the component proteins of a postsynaptic density (PSD) lattice, a core structure of the PSD of excitatory synapses in the central nervous system. "Enriched"- and "lean"-type PSD lattices were purified by synaptic plasma membrane treatment to identify the protein components by comprehensive shotgun mass spectrometry and group them into minimum essential cytoskeleton (MEC) and non-MEC components. Tubulin was found to be a major component of the MEC, with non-microtubule tubulin widely distributed on the purified PSD lattice. The presence of tubulin in and around PSDs was verified by post-embedding immunogold labeling EM of cerebral cortex. Non-MEC proteins included various typical scaffold/adaptor PSD proteins and other class PSD proteins. Thus, this study provides a new PSD lattice model consisting of non-microtubule tubulin-based backbone and various non-MEC proteins. Our findings suggest that tubulin is a key component constructing the backbone and that the associated components are essential for the versatile functions of the PSD.
Canonical versus non-canonical transsynaptic signaling of neuroligin 3 tunes development of sociality in mice. Nature communications,12(1):1848-1848 2021(Mar. 23) Author:Tomoyuki Yoshida; Atsushi Yamagata; Ayako Imai; Juhyon Kim; Hironori Izumi; Shogo Nakashima; Tomoko Shiroshima; Asami Maeda; Shiho Iwasawa-Okamoto; Kenji Azechi; Fumina Osaka; Takashi Saitoh; Katsumi Maenaka; Takashi Shimada; Yuko Fukata; Masaki Fukata; Jumpei Matsumoto; Hisao Nishijo; Keizo Takao; Shinji Tanaka; Shigeo Okabe; Katsuhiko Tabuchi; Takeshi Uemura; Masayoshi Mishina; Hisashi Mori; Shuya Fukai Abstract:Neuroligin 3 (NLGN3) and neurexins (NRXNs) constitute a canonical transsynaptic cell-adhesion pair, which has been implicated in autism. In autism spectrum disorder (ASD) development of sociality can be impaired. However, the molecular mechanism underlying NLGN3-mediated social development is unclear. Here, we identify non-canonical interactions between NLGN3 and protein tyrosine phosphatase δ (PTPδ) splice variants, competing with NRXN binding. NLGN3-PTPδ complex structure revealed a splicing-dependent interaction mode and competition mechanism between PTPδ and NRXNs. Mice carrying a NLGN3 mutation that selectively impairs NLGN3-NRXN interaction show increased sociability, whereas mice where the NLGN3-PTPδ interaction is impaired exhibit impaired social behavior and enhanced motor learning, with imbalance in excitatory/inhibitory synaptic protein expressions, as reported in the Nlgn3 R451C autism model. At neuronal level, the autism-related Nlgn3 R451C mutation causes selective impairment in the non-canonical pathway. Our findings suggest that canonical and non-canonical NLGN3 pathways compete and regulate the development of sociality.
Inhibition of CASK Expression by Virus-mediated RNA Interference in Medial Prefrontal Cortex Affects Social Behavior in the Adult Mouse Shinshu Med J,69(1):45-52-52 2021(Feb. 10) Author:Xueshan, Cao; Wen, Qiu; Bo, Pang; Mengyun, Zhou; Anuradha, Mehta; Qi, Guo; Shirai, Yoshinori; Mori, Takuma; Tabuchi, Katsuhiko Abstract:信州医学雑誌
Npas4 regulates IQSEC3 expression in hippocampal somatostatin interneurons to mediate anxiety-like behavior CELL REPORTS,36(3):109417 2021 Author:Kim, Seungjoon; Park, Dongseok; Kim, Jinhu; Kim, Dongwook; Kim, Hyeonho; Mori, Takuma; Jung, Hyeji; Lee, Dongsu; Hong, Sookyung; Jeon, Jongcheol; Tabuchi, Katsuhiko; Cheong, Eunji; Kim, Jaehoon; Um, Ji Won; Ko, Jaewon;
An Autism-Associated Neuroligin-3 Mutation Affects Developmental Synapse Elimination in the Cerebellum. Frontiers in neural circuits,15:676891-676891 2021 Author:Esther Suk King Lai; Hisako Nakayama; Taisuke Miyazaki; Takanobu Nakazawa; Katsuhiko Tabuchi; Kouichi Hashimoto; Masahiko Watanabe; Masanobu Kano Abstract:Neuroligin is a postsynaptic cell-adhesion molecule that is involved in synapse formation and maturation by interacting with presynaptic neurexin. Mutations in neuroligin genes, including the arginine to cystein substitution at the 451st amino acid residue (R451C) of neuroligin-3 (NLGN3), have been identified in patients with autism spectrum disorder (ASD). Functional magnetic resonance imaging and examination of post-mortem brain in ASD patients implicate alteration of cerebellar morphology and Purkinje cell (PC) loss. In the present study, we examined possible association between the R451C mutation in NLGN3 and synaptic development and function in the mouse cerebellum. In NLGN3-R451C mutant mice, the expression of NLGN3 protein in the cerebellum was reduced to about 10% of the level of wild-type mice. Elimination of redundant climbing fiber (CF) to PC synapses was impaired from postnatal day 10-15 (P10-15) in NLGN3-R451C mutant mice, but majority of PCs became mono-innervated as in wild-type mice after P16. In NLGN3-R451C mutant mice, selective strengthening of a single CF relative to the other CFs in each PC was impaired from P16, which persisted into juvenile stage. Furthermore, the inhibition to excitation (I/E) balance of synaptic inputs to PCs was elevated, and calcium transients in the soma induced by strong and weak CF inputs were reduced in NLGN3-R451C mutant mice. These results suggest that a single point mutation in NLGN3 significantly influences the synapse development and refinement in cerebellar circuitry, which might be related to the pathogenesis of ASD.
Inhibition of DNA ligase IV enhances the CRISPR/Cas9-mediated knock-in efficiency in mouse brain neurons. Biochemical and biophysical research communications,533(3):449-457 2020(Dec. 10) Author:Xueshan Cao; Emi Kouyama-Suzuki; Bo Pang; Taiga Kurihara; Takuma Mori; Toru Yanagawa; Yoshinori Shirai; Katsuhiko Tabuchi Abstract:CRISPR/Cas9-mediated gene knock-in in in vivo neurons using in utero electroporation is a powerful technique, but the knock-in efficiency is generally low. We previously demonstrated that co-transfection with RAD51, a key molecule of the initial step of homology-directed repair (HDR), expression vector increased EGFP knock-in efficiency in the β-actin site up to 2.5-fold in the pyramidal neurons in layer 2/3 of the somatosensory cortex of mouse brain. To further improve the efficiency, we examined the effect of inhibition of DNA ligase IV (LIG4) that is an essential molecule for non-homologous end joining (NHEJ). Co-transfection with small hairpin RNA for LIG4 (shlig4) expression vector increased the EGFP knock-in efficiency in the β-actin site up to 3.6-fold compared to the condition without shlig4. RAD51 and shlig4 expression vector co-transfection further increased the knock-in efficiency up to 4.7-fold of the control condition. These results suggest that the inhibition of LIG4 is more effective than RAD51 overexpression, and it enhances the effect of RAD51 overexpression on HDR-mediated gene knock-in in vivo neurons.
DNA repair protein RAD51 enhances the CRISPR/Cas9-mediated knock-in efficiency in brain neurons BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS,524(3):621-628-628 2020 Author:Kurihara, Taiga; Kouyama-Suzuki, Emi; Satoga, Michiru; Li, Xue; Badawi, Moataz; Thiha; Baig, Deeba Noreen; Yanagawa, Toru; Uemura, Takeshi; Mori, Takuma; Tabuchi, Katsuhiko Abstract:BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
Correction: Deficiency of calcium/calmodulin-dependent serine protein kinase disrupts the excitatory-inhibitory balance of synapses by downregulating GluN2B. Molecular psychiatry,24(7):1093-1093 2019(Jul.) Author:Takuma Mori; Enas A Kasem; Emi Suzuki-Kouyama; Xueshan Cao; Xue Li; Taiga Kurihara; Takeshi Uemura; Toru Yanagawa; Katsuhiko Tabuchi Abstract:This article was originally published under standard licence, but has now been made available under a [CC BY 4.0] license. The PDF and HTML versions of the paper have been modified accordingly.
A small number of residual teeth after the mandibular resection of oral cancer is associated With titanium reconstruction plate exposure Clin Exp Dent Res,5(5):1-7 2019(May) Author:Hiromi, Hirohata; Yanagawa, Toru; Takaoka, Shohei; Yamagata, Kenji; Sasaki, Kaoru; Shibuya, Yoichiro; Uchida, Fumihiko; Fukazawa, Satoshi; Tabuchi, Katsuhiko; Hasegawa, Shogo; Kanno; Naomi Ishibashi; Sekidou, Mitsuru; Bukawa, Hiroki Abstract:Objective: Reconstruction plates are used to treat patients with a segmental mandibular defect after oral cancer surgery. Reconstruction plate failure analysis has rarely focused on occlusion, which conducts a mechanical force to the mandible and the plate. To determine the prognostic factors, we retrospectively evaluated patients who underwent reconstruction of a mandibular segmental defect with a reconstruction plate and assessed the number of residual paired teeth. Material and Methods: From among 390 patients with oral cancer who visited University of Tsukuba Hospital (Tsukuba, Japan) between 2007 and 2017, we selected and analyzed the data of 37 patients who underwent segmental resection of the mandible and reconstruction with reconstruction plates. Prognostic factors evaluated were patient age, sex, TNM classification, plate manufacturer, treatment with radiotherapy or chemotherapy, whether the patient had diabetes or smoked, and whether the patient had a small number of residual paired teeth, plate length, and use of a fibular-free flap. Among these 37 patients, eight reconstruction plates had intraoral or extraoral exposure and were removed in 5 years. Results: Kaplan-Meier and log-rank analyses revealed that the prognosis for the 5-year plate exposure-free rate was significantly poorer for patients with a small number of residual teeth than for patients with no teeth or those with a large number of residual teeth (.01). Univariate Cox regression analysis revealed that a small number of residual teeth was a significant prognostic factor in the loss of a reconstruction plate (hazard ratio: 5.63; 95% confidence interval [1.10, 25.85]; .04). Conclusions: A small number of residual teeth after the segmental resection of oral cancer is significantly involved in reconstruction plate survival and may be important in predicting reconstruction plate prognosis.
Deficiency of calcium/calmodulin-dependent serine protein kinase disrupts the excitatory-inhibitory balance of synapses by down-regulating GluN2B. Molecular psychiatry,24(7):1079-1092 2019(Jan.) Author:Mori T; Kasem EA; Suzuki-Kouyama E; Cao X; Li X; Kurihara T; Uemura T; Yanagawa T; Tabuchi K
PTPσ Drives Excitatory Presynaptic Assembly via Various Extracellular and Intracellular Mechanisms. JOURNAL OF NEUROSCIENCE,38(30):6700-6721 2018(Jul.) Author:Han, Kyung Ah; Ko, Ji Seung; Pramanik, Gopal; Kim, Jin Young; Tabuchi, Katsuhiko; Um, Ji Won; Ko, Jaewon Abstract:JOURNAL OF NEUROSCIENCE
Synaptic-Adhesion Molecules Neurexin 1 and Neuroligin 1 as Novel Prognostic Factors in Oral Squamous Cell Carcinoma Journal of Dentistry and Dental Medicine 2018(Mar.) Author:Hiromi, Hirohata; Toru, Yanagawa; Shohei, Takaoka; Fumihiko, Uchida; Yoichiro, Shibuya; Satoru, Miyabe; Katsuhiko, Tabuchi; Yuichi, Akagi; Shogo, Hasegawa; Satoshi, Sakai; Yasutoshi, Takeuchi; Naomi, ishibashi-Kanno; Kenji, Yamagata; Hiroki, Bukawa
Neurexins and neuropsychiatric disorders NEUROSCIENCE RESEARCH,127:53-60 2018(Feb.) Author:Kasem, Enas; Kurihara, Taiga; Tabuchi, Katsuhiko Abstract:NEUROSCIENCE RESEARCH
Corrigendum to “p62 modulates the intrinsic signaling of UVB-induced apoptosis” [Journal of Dermatological Science 83 (2016) 226–233] (S0923181116300755) (10.1016/j.jdermsci.2016.05.005)) Journal of Dermatological Science,86(3):259-260 2017(Jun. 01) Author:Sachiko Ito; Shintaro Kimura; Eiji Warabi; Yasuhiro Kawachi; Masanobu Yamatoji; Fumihiko Uchida; Naomi Ishibashi-Kanno; Kenji Yamagata; Shogo Hasegawa; Junichi Shoda; Katsuhiko Tabuchi; Satoshi Sakai; Hiroki Bukawa; Mitsuru Sekido; Toru Yanagawa Abstract:The authors regret 1) Add deficiency in Abstract Error: Conclusion: p62 reduces UVB-induced apoptosis by modulating intrinsic apoptotic signaling through Src phosphorylation. Correct: Conclusion: p62 deficiency reduces UVB-induced apoptosis by modulating intrinsic apoptotic signaling through Src phosphorylation. 2) Error in spelling of Bax in 2. MATERIALS AND METHODS Error: The following primers were used: Bcl-2, forward ATGCCTTTGTGGAACTATATGGC and reverse GGTATGCACCCAGAGTGATGC
Bcl-xL, forward CAGGTGCGTGGAAAGCGTA and reverse CCTGGGTAAGGGGAGGAGT
BAX, forward AGACAGGGGCCTTTTTGCTAC and reverse AATTCGCCGGAGACACTCG
PUMA, forward AGCAGCACTTAGAGTCGCC and reverse CCGCT CGTACTGTGCG TTGAG
NOXA, forward GCAGAGCTACCACCTGAGTTC and reverse CTTTTGCGACTTCCCAGGCA
ATM, forward GATGGCTCATTTGGGCCG and reverse GTGTGGCTGATACATTTGA
and Survivin, forward ATCCACTGCCCTACCGAGAA and reverse CTTGGCTCTCTGTCTGTCCAGTT (all purchased from Greiner Bio-One International GmbH, Kremusmunster, Australia). SYBR Premix Ex Taq was purchased from TaKaRa (Tokyo, Japan). Correct: The following primers were used: Bcl-2, forward ATGCCTTTGTGGAACTATATGGC and reverse GGTATGCACCCAGAGTGATGC
Bcl-xL, forward CAGGTGCGTGGAAAGCGTA and reverse CCTGGGTAAGGGGAGGAGT
Bax, forward AGACAGGGGCCTTTTTGCTAC and reverse AATTCGCCGGAGACACTCG
PUMA, forward AGCAGCACTTAGAGTCGCC and reverse CCGCT CGTACTGTGCG TTGAG
NOXA, forward GCAGAGCTACCACCTGAGTTC and reverse CTTTTGCGACTTCCCAGGCA
ATM, forward GATGGCTCATTTGGGCCG and reverse GTGTGGCTGATACATTTGA
and Survivin, forward ATCCACTGCCCTACCGAGAA and reverse CTTGGCTCTCTGTCTGTCCAGTT (all purchased from Greiner Bio-One International GmbH, Kremusmunster, Australia). SYBR Premix Ex Taq was purchased from TaKaRa (Tokyo, Japan). 3) Error in spelling of Bax in 3. RESULTS Error: Although the expression of all of these molecules decreased after 300 mJ/cm2 UVB irradiation (Fig. 2A –D), the Bcl-2 remained significantly higher in p62−/− than in p62+/+ MEFs (P <
0.001), while the BAX was significantly lower (P <
0.001). Correct: Although the expression of all of these molecules decreased after 300 mJ/cm2 UVB irradiation (Fig. 2A–D), the Bcl-2 remained significantly higher in p62−/− than in p62+/+ MEFs (P <
0.001), while the Bax was significantly lower (P <
0.001). 4) Error in spelling of Bax in 3. RESULTS Error: Since the Bcl-2 and Bax expressions differed significantly between p62+/+ and p62−/− MEFs prior to UVB irradiation, we used real-time PCR in the steady state to examine the mRNA levels of factors associated with UV-induced apoptotic signaling [3,17–20]. In this experiment, we examined ATM, PUMA, NOXA, and survivin in addition to Bcl-2, Bcl-xL, and BAX (Fig. 3A –G). We found that the Bcl-2 and Bcl-xL mRNA levels were significantly increased in p62−/− MEFs, while those of BAX and NOXA were decreased (Fig. 3A, B, C, E). Correct: Since the Bcl-2 and Bax expressions differed significantly between p62+/+ and p62−/− MEFs prior to UVB irradiation, we used real-time PCR in the steady state to examine the mRNA levels of factors associated with UV-induced apoptotic signaling [3,17–20]. In this experiment, we examined ATM, PUMA, NOXA, and survivin in addition to Bcl-2, Bcl-xL, and Bax (Fig. 3A–G). We found that the Bcl-2 and Bcl-xL mRNA levels were significantly increased in p62−/− MEFs, while those of Bax and NOXA were decreased (Fig. 3A, B, C, E). 5) Error in spelling of Bax in Fig. 3 Error: Panel C: BAX mRNA expression in p62+/+ and p62−/− MEFs, with values of 1.00 ± 0.26 and 0.50 ± 0.07, respectively. BAX mRNA expression was significantly lower in p62−/− MEFs than in p62+/+ MEFs. Correct: Panel C: Bax mRNA expression in p62+/+ and p62−/− MEFs, with values of 1.00 ± 0.26 and 0.50 ± 0.07, respectively. Bax mRNA expression was significantly lower in p62−/− MEFs than in p62+/+ MEFs. The authors would like to apologise for any inconvenience caused.
Numbers of presynaptic Ca2+ channel clusters match those of functionally defined vesicular docking sites in single central synapses PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,114(26):E5246-E5255 2017(Jun.) Author:Takafumi Miki; Walter A. Kaufmann; Gerardo Malagon; Laura Gomez; Katsuhiko Tabuchi; Masahiko Watanabe; Ryuichi Shigemoto; Alain Marty Abstract:Many central synapses contain a single presynaptic active zone and a single postsynaptic density. Vesicular release statistics at such "simple synapses" indicate that they contain a small complement of docking sites where vesicles repetitively dock and fuse. In this work, we investigate functional and morphological aspects of docking sites at simple synapses made between cerebellar parallel fibers and molecular layer interneurons. Using immunogold labeling of SDS-treated freeze-fracture replicas, we find that Ca(v)2.1 channels form several clusters per active zone with about nine channels per cluster. The mean value and range of intersynaptic variation are similar for Ca(v)2.1 cluster numbers and for functional estimates of docking-site numbers obtained from the maximum numbers of released vesicles per action potential. Both numbers grow in relation with synaptic size and decrease by a similar extent with age between 2 wk and 4 wk postnatal. Thus, the mean docking-site numbers were 3.15 at 2 wk (range: 1-10) and 2.03 at 4 wk (range: 1-4), whereas the mean numbers of Ca(v)2.1 clusters were 2.84 at 2 wk (range: 1-8) and 2.37 at 4 wk (range: 1-5). These changes were accompanied by decreases of miniature current amplitude (from 93 pA to 56 pA), active-zone surface area (from 0.0427 mu m(2) to 0.0234 mu m(2)), and initial success rate (from 0.609 to 0.353), indicating a tightening of synaptic transmission with development. Altogether, these results suggest a close correspondence between the number of functionally defined vesicular docking sites and that of clusters of voltage-gated calcium channels.
Functions of synapse adhesion molecules neurexin/neuroligins and neurodevelopmental disorders NEUROSCIENCE RESEARCH,116:3-9 2017(Mar.) Author:Xueshan Cao; Katsuhiko Tabuchi Abstract:Neurexins and neuroligins are two distinct families of single-pass transmembrane proteins localized at pre- and postsynapses, respectively. They trans-synaptically interact with each other and induce synapse formation and maturation. Common variants and rare mutations, including copy number variations, short deletions, and single or small nucleotide changes in neurexin and neuroligin genes have been linked to the neurodevelopmental disorders, such as autism spectrum disorders (ASDs). In this review, we summarize the structure and basic synaptic function of neurexins and neuroligins, followed by behaviors and synaptic phenotypes of knock-in and knock-out mouse of these family genes. From the studies of these mice, it turns out that the effects of neurexins and neuroligins are amazingly neural circuit dependent, even within the same brain region. In addition, neurexins and neuroligins are commonly involved in the endocannabinoid signaling. These finding may provide not only insight into understanding the pathophysiology, but also the concept for strategy of therapeutic intervention for ASDs. (C) 2016 Elsevier Ireland Ltd and Japan Neuroscience Society. All rights reserved.
Distortion of the normal function of synaptic cell adhesion molecules by genetic variants as a risk for autism spectrum disorders Brain research bulletin,129(SI):82-90 2017(Mar.) Author:Baig, Deeba Noreen; Yanagawa, Toru; Tabuchi, Katsuhiko Abstract:Synaptic cell adhesion molecules (SCAMs) are a functional category of cell adhesion molecules that connect pre- and postsynapses by the protein-protein interaction via their extracellular cell adhesion domains. Countless numbers of common genetic variants and rare mutations in SCAMs have been identified in the patients with autism spectrum disorders (ASDs). Among these, NRXN and NLGN family proteins cooperatively function at synaptic terminals both of which genes are strongly implicated as risk genes for ASDs. Knock-in mice carrying a single rare point mutation of NLGN3 (NLGN3 R451C) discovered in the patients with ASDs display a deficit in social interaction and an enhancement of spatial learning and memory ability reminiscent of the clinical phenotype of ASDs. NLGN4 knockout (KO) and NRXN2α KO mice also show a deficit in sociability as well as some specific neuropsychiatric behaviors. In this review, we selected NRXNs/NLGNs, CNTNAP2/CNTNAP4, CNTN4, ITGB3, and KIRREL3 as strong ASD risk genes based on SFARI score and summarize the protein structures, functions at synapses, representative discoveries in human genetic studies, and phenotypes of the mutant model mice in light of the
Central synapse, neural circuit, and brain function NEUROSCIENCE RESEARCH,116:1-2 2017(Mar.) Author:Hideto Takahashi; Keiko Matsuda; Katsuhiko Tabuchi; Jaewon Ko
Fluorescent protein tagging of endogenous protein in brain neurons using CRISPR/Cas9-mediated knock-in and in utero electroporation techniques Scientific Reports,6(1):35861 2016(Oct.) Author:Takeshi Uemura; Takuma Mori; Taiga Kurihara; Shiori Kawase; Rie Koike; Michiru Satoga; Xueshan Cao; Xue Li; Toru Yanagawa; Takayuki Sakurai; Takayuki Shindo; Katsuhiko Tabuchi
IQ Motif and SEC7 Domain-containing Protein 3 (IQSEC3) Interacts with Gephyrin to Promote Inhibitory Synapse Formation. The Journal of biological chemistry,291(19):10119-10130 2016(Mar.) Author:Um JW; Choii G; Park D; Kim D; Jeon S; Kang H; Mori T; Papadopoulos T; Yoo T; Lee Y; Kim E; Tabuchi K; Ko J
PDZ interaction of Vangl2 links PSD-95 and Prickle2 but plays only a limited role in the synaptic localisation of Vangl2 SCIENTIFIC REPORTS,5:12916 2015(Aug.) Author:Tadahiro Nagaoka; Katsuhiko Tabuchi; Masashi Kishi Abstract:Postsynaptic density-95/Discs large/Zonula occludens-1 (PDZ) domain-mediated protein interactions play pivotal roles in various molecular biological events, including protein localisation, assembly, and signal transduction. Although the vertebrate regulator of planar cell polarity Van Gogh-like 2 (Vangl2) was recently described as a postsynaptic molecule with a PDZ-binding motif, the role of its PDZ interaction at the synapse is unknown. In this report, we demonstrate that the PDZ interaction was dispensable for the normal cluster formation of Vangl2 and not absolutely required for the synapse-associated localisation of Vangl2 in cultured hippocampal neurons. We further showed that the synaptic localisation of Vangl2 was categorised into two types: overlapping co-localisation with postsynaptic density (PSD)-95 or highly correlated but complementary pattern of association with PSD-95. Only the former was significantly sensitive to deletion of the PDZ-binding motif. In addition, the PDZ interaction enhanced the protein interactions between PSD-95 and Prickle2, which is another planar cell polarity factor that is localised at the postsynaptic density. Taken together with our recent report that the density of PSD-95 clusters was reduced in Vangl2-silenced neurons, these results suggest that Vangl2 determines the complex formation and clustering of postsynaptic molecules for synaptogenesis in mammalian brains.
β-Neurexins Control Neural Circuits by Regulating Synaptic Endocannabinoid Signaling. CELL,162(3):593-606 2015(Jul.) Author:Anderson, Garret R; Aoto, Jason; Tabuchi, Katsuhiko; Foeldy, Csaba; Covy, Jason; Yee, Ada Xin; Wu, Dick; Lee, Sung-Jin; Chen, Lu; Malenka, Robert C; Suedhof, Thomas C Abstract:alpha- and beta-neurexins are presynaptic cell-adhesion molecules implicated in autism and schizophrenia. We find that, although beta-neurexins are expressed at much lower levels than alpha-neurexins, conditional knockout of beta-neurexins with continued expression of alpha-neurexins dramatically decreased neurotransmitter release at excitatory synapses in cultured cortical neurons. The beta-neurexin knockout phenotype was attenuated by CB1-receptor inhibition, which blocks presynaptic endocannabinoid signaling, or by 2-arachidonoylglycerol synthesis inhibition, which impairs postsynaptic endocannabinoid release. In synapses formed by CA1-region pyramidal neurons onto burst-firing subiculum neurons, presynaptic in vivo knockout of beta-neurexins aggravated endocannabinoid-mediated inhibition of synaptic transmission and blocked LTP; presynaptic CB1-receptor antagonists or postsynaptic 2-arachidonoylglycerol synthesis inhibition again reversed this block. Moreover, conditional knockout of beta-neurexins in CA1-region neurons impaired contextual fear memories. Thus, our data suggest that presynaptic beta-neurexins control synaptic strength in excitatory synapses by regulating postsynaptic 2-arachidonoylglycerol synthesis, revealing an unexpected role for beta-neurexins in the endocannabinoid-dependent regulation of neural circuits.
Distinct circuit-dependent functions of presynaptic neurexin-3 at GABAergic and glutamatergic synapses NATURE NEUROSCIENCE,18(7):997-+ 2015(Jul.) Author:Jason Aoto; Csaba Foeldy; Silviana Maria Ciurea Ilcus; Katsuhiko Tabuchi; Thomas C. Suedhof Abstract:alpha- and beta-neurexins are presynaptic cell-adhesion molecules whose general importance for synaptic transmission is well documented. The specific functions of neurexins, however, remain largely unknown because no conditional neurexin knockouts are available and targeting all alpha- and beta-neurexins produced by a particular gene is challenging. Using newly generated constitutive and conditional knockout mice that target all neurexin-3 alpha and neurexin-3 beta isoforms, we found that neurexin-3 was differentially required for distinct synaptic functions in different brain regions. Specifically, we found that, in cultured neurons and acute slices of the hippocampus, extracellular sequences of presynaptic neurexin-3 mediated trans-synaptic regulation of postsynaptic AMPA receptors. In cultured neurons and acute slices of the olfactory bulb, however, intracellular sequences of presynaptic neurexin-3 were selectively required for GABA release. Thus, our data indicate that neurexin-3 performs distinct essential pre- or postsynaptic functions in different brain regions by distinct mechanisms.
PTP sigma functions as a presynaptic receptor for the glypican-4/LRRTM4 complex and is essential for excitatory synaptic transmission PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,112(6):1874-1879 2015(Feb.) Author:Ji Seung Ko; Gopal Pramanik; Ji Won Um; Ji Seon Shim; Dongmin Lee; Kee Hun Kim; Gug-Young Chung; Giuseppe Condomitti; Ho Min Kim; Hyun Kim; Joris de Wit; Kang-Sik Park; Katsuhiko Tabuchi; Jaewon Ko Abstract:Leukocyte common antigen-related receptor protein tyrosine phosphatases-comprising LAR, PTP delta, and PTP sigma-are synaptic adhesion molecules that organize synapse development. Here, we identify glypican 4 (GPC-4) as a ligand for PTP sigma. GPC-4 showed strong (nanomolar) affinity and heparan sulfate (HS)-dependent interaction with the Ig domains of PTP sigma. PTP sigma bound only to proteolytically cleaved GPC-4 and formed additional complex with leucine-rich repeat transmembrane protein 4 (LRRTM4) in rat brains. Moreover, single knockdown (KD) of PTP sigma, but not LAR, in cultured neurons significantly reduced the synaptogenic activity of LRRTM4, a postsynaptic ligand of GPC-4, in heterologous synapse-formation assays. Finally, PTP sigma KD dramatically decreased both the frequency and amplitude of excitatory synaptic transmission. This effect was reversed by wild-type PTP sigma, but not by a HS-binding-defective PTP sigma mutant. Our results collectively suggest that presynaptic PTP sigma, together with GPC-4, acts in a HS-dependent manner to maintain excitatory synapse development and function.
Mandibular reconstruction using plates prebent to fit rapid prototyping 3-dimensional printing models ameliorates contour deformity HEAD & FACE MEDICINE,10:45 2014(Oct.) Author:Masaki Azuma; Toru Yanagawa; Naomi Ishibashi-Kanno; Fumihiko Uchida; Takaaki Ito; Kenji Yamagata; Shogo Hasegawa; Kaoru Sasaki; Koji Adachi; Katsuhiko Tabuchi; Mitsuru Sekido; Hiroki Bukawa Abstract:Background: Recently, medical rapid prototyping (MRP) models, fabricated with computer-aided design and computer-aided manufacture (CAD/CAM) techniques, have been applied to reconstructive surgery in the treatment of head and neck cancers. Here, we tested the use of preoperatively manufactured reconstruction plates, which were produced using MRP models. The clinical efficacy and esthetic outcome of using these products in mandibular reconstruction was evaluated.
Methods: A series of 28 patients with malignant oral tumors underwent unilateral segmental resection of the mandible and simultaneous mandibular reconstruction. Twelve patients were treated with prebent reconstruction plates that were molded to MRP mandibular models designed with CAD/CAM techniques and fabricated on a combined powder bed and inkjet head three-dimensional printer. The remaining 16 patients were treated using conventional reconstruction methods. The surgical and esthetic outcomes of the two groups were compared by imaging analysis using post-operative panoramic tomography.
Results: The mandibular symmetry in patients receiving the MRP-model-based prebent plates was significantly better than that in patients receiving conventional reconstructive surgery.
Conclusions: Patients with head and neck cancer undergoing reconstructive surgery using a prebent reconstruction plate fabricated according to an MRP mandibular model showed improved mandibular contour compared to patients undergoing conventional mandibular reconstruction. Thus, use of this new technology for mandibular reconstruction results in an improved esthetic outcome with the potential for improved quality of life for patients.
Vascular and parenchymal amyloid pathology in an Alzheimer disease knock-in mouse model: interplay with cerebral blood flow MOLECULAR NEURODEGENERATION,9:28 2014(Aug.) Author:Hongmei Li; Qinxi Guo; Taeko Inoue; Vinicia A. Polito; Katsuhiko Tabuchi; Robert E. Hammer; Robia G. Pautler; George E. Taffet; Hui Zheng Abstract:Background: Accumulation and deposition of beta-amyloid peptides (A beta) in the brain is a central event in the pathogenesis of Alzheimer's disease (AD). Besides the parenchymal pathology, A beta is known to undergo active transport across the blood-brain barrier and cerebral amyloid angiopathy (CAA) is a prominent feature in the majority of AD. Although impaired cerebral blood flow (CBF) has been implicated in faulty A beta transport and clearance, and cerebral hypoperfusion can exist in the pre-clinical phase of Alzheimer's disease (AD), it is still unclear whether it is one of the causal factors for AD pathogenesis, or an early consequence of a multi-factor condition that would lead to AD at late stage. To study the potential interaction between faulty CBF and amyloid accumulation in clinical-relevant situation, we generated a new amyloid precursor protein (APP) knock-in allele that expresses humanized A beta and a Dutch mutation in addition to Swedish/London mutations and compared this line with an equivalent knock-in line but in the absence of the Dutch mutation, both crossed onto the PS1M146V knock-in background.
Results: Introduction of the Dutch mutation results in robust CAA and parenchymal A beta pathology, age-dependent reduction of spatial learning and memory deficits, and CBF reduction as detected by fMRI. Direct manipulation of CBF by transverse aortic constriction surgery on the left common carotid artery caused differential changes in CBF in the anterior and middle region of the cortex, where it is reduced on the left side and increased on the right side. However these perturbations in CBF resulted in the same effect: both significantly exacerbate CAA and amyloid pathology.
Conclusions: Our study reveals a direct and positive link between vascular and parenchymal A beta; both can be modulated by CBF. The new APP knock-in mouse model recapitulates many symptoms of AD including progressive vascular and parenchymal A beta pathology and behavioral deficits in the absence of APP overexpression.
Enhanced synapse remodelling as a common phenotype in mouse models of autism NATURE COMMUNICATIONS,5:4742 2014(Aug.) Author:Masaaki Isshiki; Shinji Tanaka; Toshihiko Kuriu; Katsuhiko Tabuchi; Toru Takumi; Shigeo Okabe Abstract:Developmental deficits in neuronal connectivity are considered to be present in patients with autism spectrum disorders (ASDs). Here we examine this possibility by using in vivo spine imaging in the early postnatal cortex of ASD mouse models. Spines are classified by the presence of either the excitatory postsynaptic marker PSD-95 or the inhibitory postsynaptic marker gephyrin. ASD mouse models show consistent upregulation in the dynamics of PSD-95-positive spines, which may subsequently contribute to stable synaptic connectivity. In contrast, spines receiving inputs from the thalamus, detected by the presence of gephyrin clusters, are larger, highly stable and unaffected in ASD mouse models. Importantly, two distinct mouse models, human 15q11-13 duplication and neuroligin-3 R451C point mutation, show highly similar phenotypes in spine dynamics. This selective impairment in dynamics of PSD-95-positive spines receiving intracortical projections may be a core component of early pathological changes and be a potential target of early intervention.
Peroxiredoxin I plays a protective role against UVA irradiation through reduction of oxidative stress JOURNAL OF DERMATOLOGICAL SCIENCE,74(1):9-17 2014(Apr.) Author:Takaaki Ito; Shintaro Kimura; Kahori Seto; Eiji Warabi; Yasuhiro Kawachi; Junichi Shoda; Katsuhiko Tabuchi; Kenji Yamagata; Shogo Hasegawa; Hiroki Bukawa; Tetsuro Ishii; Toru Yanagawa Abstract:Background: Exposure of skin to long-wave UV radiation (UVA) increases the cellular levels of reactive oxygen species (ROS), which have been linked to apoptosis induction through the damage of lipids, proteins, and nucleic acids. Peroxiredoxin I (Prx I) is one of a family of antioxidant proteins that plays a protective role against oxidative damage; however the role of Prx I in UVA-induced damage remains to be clarified.
Objective: Here we investigated the protective role of Prx I against UVA-induced changes using mouse embryonic fibroblasts (MEFs) derived from Prx I homozygous knockout (Prx I (-/-)) mice. Methods: Prx I (-/-) and wild-type (Prx I (+/+)) MEFs were subjected to UVA irradiation, and the resulting apoptosis was analyzed using flow cytometry, quantitative real-time PCR, and western blotting.
Results: Prx I (-/-) MEFs showed enhanced sensitivity to UVA treatment, exhibiting increased apoptosis and ROS production compared to Prx I (+/+) MEFs. Consistent with the increase in apoptosis, p53 expression was significantly higher, while Bcl-2, Bcl-xL, and Nrf2 expressions were all lower in Prx I (-/-) versus (+/+) MEFs. The UVA-induced inflammatory response was upregulated in Prx I (-/-) MEFs, as indicated by increased expressions of IkB, TNF alpha, and IL-6. Evidence was presented indicating that Prx I impacts these pathways by modifying critical signaling intermediates including p53, IkB, and Nrf2.
Conclusion: Our results indicate that Prx I plays a protective role against UVA-induced oxidative damage by controlling ROS accumulation. Both the UVA-induced apoptotic and inflammatory signals were found to be modulated by Prx I. (C) 2013 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.
Calsyntenins Function as Synaptogenic Adhesion Molecules in Concert with Neurexins CELL REPORTS,6(6):1096-1109 2014(Mar.) Author:Ji Won Um; Gopal Pramanik; Ji Seung Ko; Min-Young Song; Dongmin Lee; Hyun Kim; Kang-Sik Park; Thomas C. Suedhof; Katsuhiko Tabuchi; Jaewon Ko Abstract:Multiple synaptic adhesion molecules govern synapse formation. Here, we propose calsyntenin-3/alcadein-beta as a synapse organizer that specifically induces presynaptic differentiation in heterologous synapse-formation assays. Calsyntenin-3 (CST-3) is highly expressed during various postnatal periods of mouse brain development. The simultaneous knockdown of all three CSTs, but not CST-3 alone, decreases inhibitory, but not excitatory, synapse densities in cultured hippocampal neurons. Moreover, the knockdown of CSTs specifically reduces inhibitory synaptic transmission in vitro and in vivo. Remarkably, the loss of CSTs induces a concomitant decrease in neuron soma size in a non-cell-autonomous manner. Furthermore, alpha-neurexins (alpha-Nrxs) are components of a CST-3 complex involved in CST-3-mediated presynaptic differentiation. However, CST-3 does not directly bind to Nrxs. Viewed together, these data suggest that the three CSTs redundantly regulate inhibitory synapse formation, inhibitory synapse function, and neuron development in concert with Nrxs.
Synapse maturation and autism: Learning from Neuroligin model mice JAPANESE JOURNAL OF NEUROPSYCHOPHARMACOLOGY,34(1):1-4 2014(Feb.) Author:Katsuhiko Tabuchi; WenHsin Hang; Nur Farehan Mohamed Asgar; Gopal Pramanik Abstract:Autism is a neurodevelopmental disorder characterized by impairments in social interaction, communication, and restricted and repetitive behavior. Synaptic defects have been implicated in autism; nevertheless, the cause is still largely unknown. A mutation that substitutes cysteine for arginine at residue 451 of Neuroligin-3 (R451C) is the first monogenic mutation identified in idiopathic autism patients. To study the relationship between this mutation and autism, we generated knock-in mice that recapitulated this mutation. The knock-in mice were born and grew up normally without showing any major physical phenotypes, but showed a deficit in social interaction. We studied synaptic function in the layer Will pyramidal neurons in the somatosensory cortex and found inhibitory synaptic transmission was enhanced in the knock-in mice. The administration of GABA blocker rescued social interaction, suggesting that this caused autistic behavior in these mice. We also found, by Morris water maze test, that spatial learning and memory were significantly enhanced in the knock-in mice. Electrophysiology in the CA1 region of the hippocampus revealed that LTP, the NMDA/AMPA ratio, and NR2B function were enhanced, indicating that synaptic maturation was impaired in the knock-in mice. This may cause the deficit in social behavior and extraordinary memory ability occasionally seen in autistic patients.
Presynaptic Neurexin-3 Alternative Splicing trans-Synaptically Controls Postsynaptic AMPA Receptor Trafficking CELL,154(1):75-88 2013(Jul.) Author:Jason Aoto; David C. Martinelli; Robert C. Malenka; Katsuhiko Tabuchi; Thomas C. Suedhof Abstract:Neurexins are essential presynaptic cell adhesion molecules that are linked to schizophrenia and autism and are subject to extensive alternative splicing. Here, we used a genetic approach to test the physiological significance of neurexin alternative splicing. We generated knockin mice in which alternatively spliced sequence #4 (SS4) of neuexin-3 is constitutively included but can be selectively excised by cre-recombination. SS4 of neurexin-3 was chosen because it is highly regulated and controls neurexin binding to neuroligins, LRRTMs, and other ligands. Unexpectedly, constitutive inclusion of SS4 in presynaptic neurexin-3 decreased postsynaptic AMPA, but not NMDA receptor levels, and enhanced postsynaptic AMPA receptor endocytosis. Moreover, constitutive inclusion of SS4 in presynaptic neurexin-3 abrogated postsynaptic AMPA receptor recruitment during NMDA receptor-dependent LTP. These phenotypes were fully rescued by constitutive excision of SS4 in neurexin-3. Thus, alternative splicing of presynaptic neurexin-3 controls postsynaptic AMPA receptor trafficking, revealing an unanticipated alternative splicing mechanism for trans-synaptic regulation of synaptic strength and long-term plasticity.
Neuroligin-1 controls synaptic abundance of NMDA-type glutamate receptors through extracellular coupling PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,110(2):725-730 2013(Jan.) Author:Elaine C. Budreck; Oh-Bin Kwon; Jung Hoon Jung; Stephane Baudouin; Albert Thommen; Hye-Sun Kim; Yugo Fukazawa; Harumi Harada; Katsuhiko Tabuchi; Ryuichi Shigemoto; Peter Scheiffele; Joung-Hun Kim Abstract:Despite the pivotal functions of the NMDA receptor (NMDAR) for neural circuit development and synaptic plasticity, the molecular mechanisms underlying the dynamics of NMDAR trafficking are poorly understood. The cell adhesion molecule neuroligin-1 (NL1) modifies NMDAR-dependent synaptic transmission and synaptic plasticity, but it is unclear whether NL1 controls synaptic accumulation or function of the receptors. Here, we provide evidence that NL1 regulates the abundance of NMDARs at postsynaptic sites. This function relies on extracellular, NL1 isoform-specific sequences that facilitate biochemical interactions between NL1 and the NMDAR GluN1 subunit. Our work uncovers NL1 isoform-specific cis-interactions with ionotropic glutamate receptors as a key mechanism for controlling synaptic properties.
Soluble amyloid precursor protein (APP) regulates transthyretin and Klotho gene expression without rescuing the essential function of APP (vol 107, pg 17362, 2010) PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,110(32):13228-13228 2013 Author:Li, Hongmei; Wang, Baiping; Wang, Zilai; Guo, Qinxi; Tabuchi, Katsuhiko; Hammer, Robert E; Suedhof, Thomas C; Zheng, Hui Abstract:PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
A novel method for evaluating postsurgical results of unilateral cleft lip and palate with the use of Hausdorff distance: presurgical orthopedic treatment improves nasal symmetry after primary cheiloplasty ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY ORAL RADIOLOGY,114(6):704-711 2012(Dec.) Author:Rei Karube; Hiroyoshi Sasaki; Shinji Togashi; Toru Yanagawa; Shizuo Nakane; Naomi Ishibashi; Kenji Yamagata; Kojiro Onizawa; Koji Adachi; Katsuhiko Tabuchi; Mitsuru Sekido; Hiroki Bukawa Abstract:Objective. To evaluate surgery results, we established a novel method to digitize nasal morphology with the use of Hausdorff distance and analyzed nose morphology after cheiloplasty.
Study Design. We evaluated the naris after primary cheiloplasty of 30 unilateral cleft lip and palate patients. Similarity between left and right sides was assessed by visual evaluation, area ratio, perimeter ratio, aspect a/u ratio, and Hausdorff distance. The postoperative naris morphology was also compared between 15 patients treated with a Hotz plate before surgery and 15 not treated.
Results. Significant correlation with visual evaluation was found for Hausdorff distance. For the groups with and without Hotz plate treatment, the visual evaluation was higher and Hausdorff distance significantly lower in the treated group.
Conclusions. The morphologic measurement obtained using the Hausdorff distance was the closest to visual evaluation, and assessment using Hausdorff distance suggested that using a Hotz plate helps retain the symmetry of the nares after cheiloplasty. (Oral Surg Oral Med Oral Pathol Oral Radiol 2012;114:704-711)
Presurgical Nasoalveolar Molding Orthopedic Treatment Improves the Outcome of Primary Cheiloplasty of Unilateral Complete Cleft Lip and Palate, as Assessed by Naris Morphology and Cleft Gap JOURNAL OF CRANIOFACIAL SURGERY,23(6):1596-1601 2012(Nov.) Author:Hiroyoshi Sasaki; Shinji Togashi; Rei Karube; Toru Yanagawa; Shizuo Nakane; Katsuhiko Tabuchi; Naomi Ishibashi; Yoshiko Shinya; Hiroyuki Ito; Kenji Yamagata; Kojiro Onizawa; Koji Adachi; Mitsuru Sekido; Hiroki Bukawa Abstract:We evaluated the effects of presurgical nasoalveolar molding (NAM) with an orthopedic appliance and compared them with a passive orthopedic method (Hotz plate, HP), focusing on the naris morphology and width of the alveolar and palate cleft gap. The subjects were 28 unilateral complete cleft lip and palate patients treated with primary cheiloplasty at Tsukuba University Hospital from 2004 to 2011. Thirteen patients were treated preoperatively with NAM (NAM group), and 15 with HP (HP group). The surgical outcome was assessed according to left-right naris symmetry, as measured by the area ratio, perimeter ratio, aspect a/u ratio (aspect ratio of the affected side/aspect ratio of the unaffected side), and Hausdorff distance. In addition, the alveolar and palate cleft width was measured at the times of orthopedic plate setting and primary cheiloplasty. The aspect ratio was significantly smaller in the NAM group than in the HP group before the operation. In both groups, the aspect ratio, perimeter ratio, and Hausdorff distance were significantly smaller after the operation than before. The width of the alveolar and palate cleft gap was significantly narrowed in the NAM group, and the cleft gap at the initiation of NAM correlated significantly with the Hausdorff distance after cheiloplasty. We found that NAM improved the form of the naris after primary cheiloplasty and decreased the palate cleft gap more effectively than HP and that the width of the palate cleft gap was correlated with the surgical outcome of the naris.
Analysis of Neuroligin-3 R451C knock-in mice as models for autistic savant 日本生物学的精神医学会誌,23(4):281-286 2012 Author:Baig Deeba Noreen; 柳川 徹; 田渕 克彦 Abstract:Neuroligin（NLGN）は，シナプス後終末に局在する1回膜貫通型細胞接着因子で，シナプス前終末に局在するNeurexin（NRXN）と結合することにより，シナプスの成熟を誘導すると考えられている。近年，NLGN およびNRXNの遺伝子異常が自閉症患者のスクリーニングから頻繁に発見されるようになったことから，これらの分子によって維持される正常なシナプス機能の破綻が，少なくとも一部の自閉症の原因と関係しているのではないかと考えられるようになってきた。我々は，ヒトの自閉症患者から最初に発見されたNLGNの単一アミノ酸変異である，NLGN 3タンパク質の451 番目のアルギニンがシステインに置換された変異を有するマウスを作成し，解析を行った。このマウスは正常に発生，成長し，目立った外見的異常は見られなかったが，行動解析により，自閉症特有の社会的相互作用の異常を再現することが証明された。また，Morris水迷路試験により，この変異マウスでは空間学習記憶能力が顕著に亢進することも見出した。このマウスの大脳皮質のシナプス機能を電気生理学的に解析したところ，抑制性シナプス機能の増強が認められ，GABA受容体遮断薬投与によってこのマウスの社会的相互作用の異常が改善されたことから，このマウスでは大脳皮質の抑制性シナプス機能の増強が，社会的相互作用の異常を引き起こしていることが示唆された。このマウスの海馬のシナプス機能を調べたところ，このマウスではシナプスの可塑性の亢進が認められ，NMDA受容体のうち，幼若型シナプスで特徴的な，NR2Bサブユニットの比率が優位になっていることを見出した。NR2Bの過剰発現マウスでは学習記憶能力が亢進する過去の知見と一致する。以上のことより，NLGN 3 R451C変異は，シナプスの成熟異常を起こし，大脳皮質機能を介した社会的相互作用の異常と，海馬機能を介した学習記憶能力の亢進という，ある種の自閉症の症状のパターンを生み出す原因になっていると考えられる。
Autism-linked neuroligin-3 R451C mutation differentially alters hippocampal and cortical synaptic function PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,108(33):13764-13769 2011(Aug.) Author:Mark Etherton; Csaba Foeldy; Manu Sharma; Katsuhiko Tabuchi; Xinran Liu; Mehrdad Shamloo; Robert C. Malenka; Thomas C. Suedhof Abstract:Multiple independent mutations in neuroligin genes were identified in patients with familial autism, including the R451C substitution in neuroligin-3 (NL3). Previous studies showed that NL3(R451C) knock-in mice exhibited modestly impaired social behaviors, enhanced water maze learning abilities, and increased synaptic inhibition in the somatosensory cortex, and they suggested that the behavioral changes in these mice may be caused by a general shift of synaptic transmission to inhibition. Here, we confirm that NL3(R451C) mutant mice behaviorally exhibit social interaction deficits and electrophysiologically display increased synaptic inhibition in the somatosensory cortex. Unexpectedly, however, we find that the NL3(R451C) mutation produced a strikingly different phenotype in the hippocampus. Specifically, in the hippocampal CA1 region, the NL3(R451C) mutation caused an similar to 1.5-fold increase in AMPA receptor-mediated excitatory synaptic transmission, dramatically altered the kinetics of NMDA receptor-mediated synaptic responses, induced an approximately twofold up-regulation of NMDA receptors containing NR2B subunits, and enhanced long-term potentiation almost twofold. NL3 KO mice did not exhibit any of these changes. Quantitative light microscopy and EM revealed that the NL3(R451C) mutation increased dendritic branching and altered the structure of synapses in the stratum radiatum of the hippocampus. Thus, in NL3(R451C) mutant mice, a single point mutation in a synaptic cell adhesion molecule causes context-dependent changes in synaptic transmission; these changes are consistent with the broad impact of this mutation on murine and human behaviors, suggesting that NL3 controls excitatory and inhibitory synapse properties in a region-and circuit-specific manner.
An autism-associated point mutation in the neuroligin cytoplasmic tail selectively impairs AMPA receptor-mediated synaptic transmission in hippocampus EMBO JOURNAL,30(14):2908-2919 2011(Jul.) Author:Mark R. Etherton; Katsuhiko Tabuchi; Manu Sharma; Jaewon Ko; Thomas C. Suedhof Abstract:Neuroligins are evolutionarily conserved postsynaptic cell-adhesion molecules that function, at least in part, by forming trans-synaptic complexes with presynaptic neurexins. Different neuroligin isoforms perform diverse functions and exhibit distinct intracellular localizations, but contain similar cytoplasmic sequences whose role remains largely unknown. Here, we analysed the effect of a single amino-acid substitution (R704C) that targets a conserved arginine residue in the cytoplasmic sequence of all neuroligins, and that was associated with autism in neuroligin-4. We introduced the R704C mutation into mouse neuroligin-3 by homologous recombination, and examined its effect on synapses in vitro and in vivo. Electrophysiological and morphological studies revealed that the neuroligin-3 R704C mutation did not significantly alter synapse formation, but dramatically impaired synapse function. Specifically, the R704C mutation caused a major and selective decrease in AMPA receptor-mediated synaptic transmission in pyramidal neurons of the hippocampus, without similarly changing NMDA or GABA receptor-mediated synaptic transmission, and without detectably altering presynaptic neurotransmitter release. Our results suggest that the cytoplasmic tail of neuroligin-3 has a central role in synaptic transmission by modulating the recruitment of AMPA receptors to postsynaptic sites at excitatory synapses. The EMBO Journal ( 2011) 30, 2908-2919. doi: 10.1038/emboj.2011.182; Published online 3 June 2011
Soluble amyloid precursor protein (APP) regulates transthyretin and Klotho gene expression without rescuing the essential function of APP PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,107(40):17362-17367 2010(Oct.) Author:Hongmei Li; Baiping Wang; Zilai Wang; Qinxi Guo; Katsuhiko Tabuchi; Robert E. Hammer; Thomas C. Suedhof; Hui Zheng Abstract:Amyloidogenic processing of the amyloid precursor protein (APP) generates a large secreted ectodomain fragment (APPs beta), beta-amyloid (A beta) peptides, and an APP intracellular domain (AICD). Whereas A beta is viewed as critical for Alzheimer's disease pathogenesis, the role of other APP processing products remains enigmatic. Of interest, the AICD has been implicated in transcriptional regulation, and N-terminal cleavage of APPs beta has been suggested to produce an active fragment that may mediate axonal pruning and neuronal cell death. We previously reported that mice deficient in APP and APP-like protein 2 (APLP2) exhibit early postnatal lethality and neuromuscular synapse defects, whereas mice with neuronal conditional deletion of APP and APLP2 are viable. Using transcriptional profiling, we now identify transthyretin (TTR) and Klotho as APP/APLP2-dependent genes whose expression is decreased in loss-of-function states but increased in gain-of-function states. Significantly, by creating an APP knockin allele that expresses only APPs beta protein, we demonstrate that APPs beta is not normally cleaved in vivo and is fully capable of mediating the APP-dependent regulation of TTR and Klotho gene expression. Despite being an active regulator of gene expression, APPs beta did not rescue the lethality and neuromuscular synapse defects of APP and APLP2 double-KO animals. Our studies identify TTR and Klotho as physiological targets of APP that are regulated by soluble APPs beta independent of developmental APP functions. This unexpected APP-mediated signaling pathway may play an important role in maintaining TTR and Klotho levels and their respective functions in A beta sequestration and aging.
Genetic Dissection of the Amyloid Precursor Protein in Developmental Function and Amyloid Pathogenesis JOURNAL OF BIOLOGICAL CHEMISTRY,285(40):30598-30605 2010(Oct.) Author:Hongmei Li; Zilai Wang; Baiping Wang; Qinxi Guo; Georgia Dolios; Katsuhiko Tabuchi; Robert E. Hammer; Thomas C. Suedhof; Rong Wang; Hui Zheng Abstract:Proteolytic processing of the amyloid precursor protein (APP) generates large soluble APP derivatives, beta-amyloid (A beta) peptides, and APP intracellular domain. Expression of the extracellular sequences of APP or its Caenorhabditis elegans counterpart has been shown to be sufficient in partially rescuing the CNS phenotypes of the APP-deficient mice and the lethality of the apl-1 null C. elegans, respectively, leaving open the question as what is the role of the highly conserved APP intracellular domain? To address this question, we created an APP knock-in allele in which the mouse A beta sequence was replaced by the human A beta. A frameshift mutation was introduced that replaced the last 39 residues of the APP sequence. We demonstrate that the C-terminal mutation does not overtly affect APP processing and amyloid pathology. In contrast, crossing the mutant allele with APP-like protein 2 (APLP2)-null mice results in similar neuromuscular synapse defects and early postnatal lethality as compared with mice doubly deficient in APP and APLP2, demonstrating an indispensable role of the APP C-terminal domain in these development activities. Our results establish an essential function of the conserved APP intracellular domain in developmental regulation, and this activity can be genetically uncoupled from APP processing and A beta pathogenesis.
Neuroligin-1 Deletion Results in Impaired Spatial Memory and Increased Repetitive Behavior JOURNAL OF NEUROSCIENCE,30(6):2115-2129 2010(Feb.) Author:Jacqueline Blundell; Cory A. Blaiss; Mark R. Etherton; Felipe Espinosa; Katsuhiko Tabuchi; Christopher Walz; Marc F. Bolliger; Thomas C. Suedhof; Craig M. Powell Abstract:Neuroligins (NLs) are a family of neural cell-adhesion molecules that are involved in excitatory/inhibitory synapse specification. Multiple members of the NL family (including NL1) and their binding partners have been linked to cases of human autism and mental retardation. We have now characterized NL1-deficient mice in autism-and mental retardation-relevant behavioral tasks. NL1 knock-out (KO) mice display deficits in spatial learning and memory that correlate with impaired hippocampal long-term potentiation. In addition, NL1 KO mice exhibit a dramatic increase in repetitive, stereotyped grooming behavior, a potential autism-relevant abnormality. This repetitive grooming abnormality in NL1 KO mice is associated with a reduced NMDA/AMPA ratio at corticostriatal synapses. Interestingly, we further demonstrate that the increased repetitive grooming phenotype can be rescued in adult mice by administration of the NMDA receptor partial coagonist D-cycloserine. Broadly, these data are consistent with a role of synaptic cell-adhesion molecules in general, and NL1 in particular, in autism and implicate reduced excitatory synaptic transmission as a potential mechanism and treatment target for repetitive behavioral abnormalities.
Disruption of LGI1-linked synaptic complex causes abnormal synaptic transmission and epilepsy PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,107(8):3799-3804 2010(Feb.) Author:Yuko Fukata; Kathryn L. Lovero; Tsuyoshi Iwanaga; Atsushi Watanabe; Norihiko Yokoi; Katsuhiko Tabuchi; Ryuichi Shigemoto; Roger A. Nicoll; Masaki Fukata Abstract:Epilepsy is a devastating and poorly understood disease. Mutations in a secreted neuronal protein, leucine-rich glioma inactivated 1 (LGI1), were reported in patients with an inherited form of human epilepsy, autosomal dominant partial epilepsy with auditory features (ADPEAF). Here, we report an essential role of LGI1 as an antiepileptogenic ligand. We find that loss of LGI1 in mice (LGI1(-/-)) causes lethal epilepsy, which is specifically rescued by the neuronal expression of LGI1 transgene, but not LGI3. Moreover, heterozygous mice for the LGI1 mutation (LGI1(+/-)) show lowered seizure thresholds. Extracellularly secreted LGI1 links two epilepsy-related receptors, ADAM22 and ADAM23, in the brain and organizes a transsynaptic protein complex that includes presynaptic potassium channels and postsynaptic AMPA receptor scaffolds. A lack of LGI1 disrupts this synaptic protein connection and selectively reduces AMPA receptor-mediated synaptic transmission in the hippocampus. Thus, LGI1 may serve as a major determinant of brain excitation, and the LGI1 gene-targeted mouse provides a good model for human epilepsy.
Conditional Forebrain Inactivation of Nicastrin Causes Progressive Memory Impairment and Age-Related Neurodegeneration JOURNAL OF NEUROSCIENCE,29(22):7290-7301 2009(Jun.) Author:Katsuhiko Tabuchi; Guiquan Chen; Thomas C. Suedhof; Jie Shen Abstract:Loss of presenilin function in adult mouse brains causes memory loss and age-related neurodegeneration. Since presenilin possesses gamma-secretase-dependent and -independent activities, it remains unknown which activity is required for presenilin-dependent memory formation and neuronal survival. To address this question, we generated postnatal forebrain-specific nicastrin conditional knock-out (cKO) mice, in which nicastrin, a subunit of gamma-secretase, is inactivated selectively in mature excitatory neurons of the cerebral cortex. nicastrin cKO mice display progressive impairment in learning and memory and exhibit age-dependent cortical neuronal loss, accompanied by astrocytosis, microgliosis, and hyperphosphorylation of the microtubule-associated protein Tau. The neurodegeneration observed in nicastrin cKO mice likely occurs via apoptosis, as evidenced by increased numbers of apoptotic neurons. These findings demonstrate an essential role of nicastrin in the execution of learning and memory and the maintenance of neuronal survival in the brain and suggest that presenilin functions in memory and neuronal survival via its role as a gamma-secretase subunit.
Increased anxiety-like behavior in mice lacking the inhibitory synapse cell adhesion molecule neuroligin 2 GENES BRAIN AND BEHAVIOR,8(1):114-126 2009(Feb.) Author:J. Blundell; K. Tabuchi; M. F. Bolliger; C. A. Blaiss; N. Brose; X. Liu; T. C. Sudhof; C. M. Powell Abstract:Neuroligins (NL) are postsynaptic cell adhesion molecules that are thought to specify synapse properties. Previous studies showed that mutant mice carrying an autism-associated point mutation in NL3 exhibit social interaction deficits, enhanced inhibitory synaptic function and increased staining of inhibitory synaptic puncta without changes in overall inhibitory synapse numbers. In contrast, mutant mice lacking NL2 displayed decreased inhibitory synaptic function. These studies raised two relevant questions. First, does NL2 deletion impair inhibitory synaptic function by altering the number of inhibitory synapses, or by changing their efficacy? Second, does this effect of NL2 deletion on inhibition produce behavioral changes? We now show that although NL2-deficient mice exhibit an apparent decrease in number of inhibitory synaptic puncta, the number of symmetric synapses as determined by electron microscopy is unaltered, suggesting that NL2 deletion impairs the function of inhibitory synapses without decreasing their numbers. This decrease in inhibitory synaptic function in NL2-deficient mice correlates with a discrete behavioral phenotype that includes a marked increase in anxiety-like behavior, a decrease in pain sensitivity and a slight decrease in motor co-ordination. This work confirms that NL2 modulates inhibitory synaptic function and is the first demonstration that global deletion of NL2 can lead to a selective behavioral phenotype.
Neuroligin-3 mutation implicated in autism increases inhibitory synaptic transmission in mice SCIENCE,318(5847):71-76 2007(Oct.) Author:Katsuhiko Tabuchi; Jacqueline Blundell; Mark R. Etherton; Robert E. Hammer; Xinran Liu; Craig M. Powell; Thomas C. Suedhof Abstract:Autism spectrum disorders (ASDs) are characterized by impairments in social behaviors that are sometimes coupled to specialized cognitive abilities. A small percentage of ASD patients carry mutations in genes encoding neuroligins, which are postsynaptic cell-adhesion molecules. We introduced one of these mutations into mice: the Arg(451)-> Cys(451) (R451C) substitution in neuroligin-3. R451C mutant mice showed impaired social interactions but enhanced spatial learning abilities. Unexpectedly, these behavioral changes were accompanied by an increase in inhibitory synaptic transmission with no apparent effect on excitatory synapses. Deletion of neuroligin-3, in contrast, did not cause such changes, indicating that the R451C substitution represents a gain-of-function mutation. These data suggest that increased inhibitory synaptic transmission may contribute to human ASDs and that the R451C knockin mice may be a useful model for studying autism-related behaviors.
Loss of cytokeratin 13 expression in squamous cell carcinoma of the tongue is a possible sign for local recurrence JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH,26(2):215-220 2007(Jun.) Author:T. Yanagawa; H. Yoshida; K. Yamagata; K. Onizawa; K. Tabuchi; Y. Koyama; S. Iwasa; H. Shimoyamada; H. Harada; K. Omura Abstract:Cytokeratin (CK) 13 is an intermediate filament protein that is expressed in a cell-type-specific manner, in the tongue and occasionally in tongue squamous cell carcinoma (SCC). Correlations between the clinical features of patients with SCC and CK13 expression in the tumor are here investigated along with CK13's utility as a marker for tongue cancer status. Samples from 121 patients with SCC of the tongue were examined by immunohistochemistry with antibodies against CK13. Correlations between the expression level of CK13 in the tumor and the patients' clinical features were statistically analyzed by univariate and multivariate methods. Univariate analysis showed a more relevant number of local recurrence (P=0.04) in CK13-negative staining patients. In addition, CK13-negative cases were associated with local recurrence by multiple logistic regression analysis (OR: 3.36; 95% Cl: 1.044-10.78; P = 0.04). Our results suggest that the loss of CK13 expression indicates tumors with a high potential for recurrence, and thus CK13 could be useful for determining the best course of treatment.
Deletion of alpha-neurexins does not cause a major impairment of axonal pathfinding or synapse formation JOURNAL OF COMPARATIVE NEUROLOGY,502(2):261-274 2007(May) Author:Irina Dudanova; Katsuhiko Tabuchi; Astrid Rohlmann; Thomas C. Suedhof; Markus Missler Abstract:alpha-Neurexins are synaptic cell-surface molecules that are required for Ca2+-triggered exocytosis. Mice lacking all three alpha-neurexins show drastically reduced neurotransmitter release at excitatory and inhibitory synapses and die early postnatally. Although previous histological analysis of newborn a-neurexin triple mutants revealed only a moderate reduction in the density of type II synapses in the brainstem, cell culture studies proposed that neurexins are prominently involved in synapse formation. To assess the contribution of a-neurexins to the formation and structural properties of synapses in vivo, we performed a detailed morphological analysis of the brains from surviving adult double knockout mice lacking two of the three a-neurexins. Despite their impaired neurotransmission, we did not observe any gross anatomical defects or changes in the distribution of synaptic proteins in adult mutants. Only mild structural alterations were found: a similar to 20% reduction of neuropil area in many brain regions, resulting predominantly from shortened distal dendritic branches and fewer spines, as demonstrated by Golgi impregnation of pyramidal neurons. Quantitative electron microscopy revealed ultrastructurally normal type I and II terminals and a similar to 30% decrease in the density of type II synapses in the neocortex. To exclude errors in pathfinding, we investigated axonal projections in the olfactory bulb of newborn knockouts and did not observe any changes. Therefore, a-neurexins are not essential for the formation of the vast majority of synapses in vivo but rather regulate the function of these synapses.
Genetic analysis of Mint/X11 proteins: Essential presynaptic functions of a neuronal adaptor protein family JOURNAL OF NEUROSCIENCE,26(50):13089-13101 2006(Dec.) Author:Angela Ho; Wade Morishita; Deniz Atasoy; Xinran Liu; Katsuhiko Tabuchi; Robert E. Hammer; Robert C. Malenka; Thomas C. Sudhof Abstract:Mints/X11s are adaptor proteins composed of three isoforms: neuron-specific Mints 1 and 2, and the ubiquitously expressed Mint 3. We have now analyzed constitutive and conditional knock-out mice for all three Mints/X11s. We found that similar to 80% of mice lacking both neuron-specific Mint isoforms (Mints 1 and 2) die at birth, whereas mice lacking any other combination of Mint isoforms survive normally. The similar to 20% surviving Mint 1/2 double knock-out mice exhibit a decrease in weight and deficits in motor behaviors. Hippocampal slice electrophysiology uncovered a decline in spontaneous neurotransmitter release, lowered synaptic strength, and enhanced paired-pulse facilitation in Mint-deficient mice, suggesting a decreased presynaptic release probability. Acute ablation of Mint expression in cultured neurons from conditional Mint 1/2/3 triple knock-in mice also revealed a decline in spontaneous release, confirming that deletion of Mints impair presynaptic function. Quantitation of synaptic proteins showed that acute deletion of Mints caused a selective increase in Munc18-1 and Fe65 proteins, and overexpression of Munc18-1 in wild-type neurons also produced a decrease in spontaneous release, suggesting that the interaction of Mints with Munc18-1 may contribute to the presynaptic phenotype observed in Mint-deficient mice. Our studies thus indicate that Mints are important regulators of presynaptic neurotransmitter release that are essential for mouse survival.
Nicastrin functions as a gamma-secretase-substrate receptor CELL,122(3):435-447 2005(Aug.) Author:S Shah; SF Lee; K Tabuchi; YH Hao; C Yu; Q LaPlant; H Ball; CE Dann; T Sudhof; G Yu Abstract:gamma-secretase catalyzes the intramembrane cleavage of amyloid precursor protein (APP) and Notch after their extracellular domains are shed by site-specific proteolysis. Nicastrin is an essential glycoprotein component of the gamma-secretase complex but has no known function. We now show that the ectodomain of nicastrin binds the new amino terminus that is generated upon proteolysis of the extracellular APP and Notch domains, thereby recruiting the APP and Notch substrates into the gamma-secretase complex. Chemicalor anti body-mediated blocking of the free amino terminus, addition of purified nicastrin ectodomain, or mutations in the ectodomain markedly reduce the binding and cleavage of substrate by gamma-secretase. These results indicate that nicastrin is a receptor for the amino-terminal stubs that are generated by ectodomain shedding of type I transmembrane proteins. Our data are consistent with a model where nicastrin presents these substrates toy-secretase and thereby facilitates their cleavage via intramembrane proteolysis.
Differences in care-seeking behavior for acute chest pain in the United States and Japan AMERICAN HEART JOURNAL,147(4):630-635 2004(Apr.) Author:L Liao; DJ Whellan; K Tabuchi; KA Schulman Abstract:Background Delay from onset of acute myocardial infarction symptoms to the delivery of medical care is a major determinant of prognosis. Although studies have explored patient factors for delay in seeking care, there are limited data on international differences in care-seeking behavior.
Methods We surveyed 1032 people in the United States and 1422 people in Japan in January 1997 on decision-making responses to a chest pain scenario representing acute MI. Participants were asked about how they would seek initial care and how promptly they would seek care.
Results The mean age was 43.6 years in the United States and 48.3 years in Japan. For the hypothetical scenario, US respondents were more likely to seek care at an emergency department (22.9% vs 16.2% in Japan) or through emergency medical services/911 (55.9% vs 32.9% in Japan, P =.001). American subjects were also more likely to seek care immediately (83.1% vs 56.4% in Japan, P =.001).
Conclusion Respondents in the United States and Japan differed substantially in their responses to a hypothetical chest pain scenario. Whether these differences result from cultural or health care system factors and whether these apparent attitudes produce gaps in real responses to acute coronary syndromes must be explored in further studies.
Drosophila homeodomain protein REPO controls glial differentiation by cooperating with ETS and BTB transcription factors DEVELOPMENT,130(11):2419-2428 2003(Jun.) Author:Y Yuasa; M Okabe; S Yoshikawa; K Tabuchi; WC Xiong; Y Hiromi; H Okano Abstract:In Drosophila, cell-fate determination of all neuroectoderm-derived glial cells depends on the transcription factor Glial cells missing (GCM), which serves as a binary switch between the neuronal and glial cell fates. Because the expression of GCM is restricted to the early phase of glial development, other factors must be responsible for the terminal differentiation of glial cells. Expression of three transcription factors, Reversed Polarity (REPO), Tramtrack p69 (TTK69) and PointedP1 (PNTP1), is induced by GCM in glial cells. REPO is a paired-like homeodomain protein, expressed exclusively in glial cells, and is required for the migration and differentiation of embryonic glial cells. To understand how REPO functions in glial terminal differentiation, we have analyzed the mechanism of gene regulation by REPO. We show that REPO can act as a transcriptional activator through the CAATTA motif in glial cells, and define three genes whose expression in vivo depends on REPO function. In different types of glial cells, REPO can act alone, or cooperate with either TTK69 or PNTP1 to regulate different target genes. Coordination of target gene expression by these three transcription factors may contribute to the diversity of glial cell types. In addition to promoting glial differentiation, we found that REPO is also necessary to suppress neuronal development, cooperating with TTK69. We propose that REPO plays a key role in both glial development and diversification.
Structure and evolution of neurexin genes: Insight into the mechanism of alternative splicing GENOMICS,79(6):849-859 2002(Jun.) Author:K Tabuchi; TC Sudhof Abstract:Neurexins are neuron-specific vertebrate proteins with hundreds of differentially spliced isoforms that may function in synapse organization. We now show that Drosophila melanogaster and Caenorhabditis elegans express a single gene encoding only an alpha-neurexin, whereas humans and mice express three genes, each of which encodes alpha- and beta-neurexins transcribed from separate promoters. The neurexin genes are very large (up to 1.62 Mb), with the neurexin-3 gene occupying almost 2% of human chromosome 14. Although invertebrate and vertebrate neurexins exhibit a high degree of evolutionary conservation, only vertebrate neurexins are subject to extensive alternative splicing that uses mechanisms ranging from strings of mini-exons to multiple alternative splice donor and acceptor sites. Consistent with their proposed role in synapse specification, neurexins thus have evolved from relatively simple genes in invertebrates to diversified genes in vertebrates with multiple promoters and extensive alternative splicing.
CASK participates in alternative tripartite complexes in which Mint 1 competes for binding with Caskin 1, a novel CASK-binding protein JOURNAL OF NEUROSCIENCE,22(11):4264-4273 2002(Jun.) Author:K Tabuchi; T Biederer; S Butz; TC Sudhof Abstract:CASK, an adaptor protein of the plasma membrane, is composed of an N-terminal calcium/calmodulin-dependent protein (CaM) kinase domain, central PSD-95, Dlg, and ZO-1/2 domain (PDZ) and Src homology 3 (SH3) domains, and a C-terminal guanylate kinase sequence. The CaM kinase domain of CASK binds to Mint 1, and the region between the CaM kinase and PDZ domains interacts with Velis, resulting in a tight tripartite complex. CASK, Velis, and Mint 1 are evolutionarily conserved in Caenorhabditis elegans, in which homologous genes (called lin-2, lin-7, and lin-10) are required for vulva development. We now demonstrate that the N-terminal CaM kinase domain of CASK binds to a novel brain-specific adaptor protein called Caskin 1. Caskin 1 and a closely related isoform, Caskin 2, are multidomain proteins containing six N-terminal ankyrin repeats, a single SH3 domain, and two sterile alpha motif domains followed by a long proline-rich sequence and a short conserved C-terminal domain. Unlike CASK and Mint 1, no Caskin homolog was detected in C. elegans. Immunoprecipitations showed that Caskin 1, like Mint 1, is stably bound to CASK in the brain. Affinity chromatography experiments demonstrated that Caskin 1 coassembles with CASK on the immobilized cytoplasmic tail of neurexin 1, suggesting that CASK and Caskin 1 coat the cytoplasmic tails of neurexins and other cell-surface proteins. Detailed mapping studies revealed that Caskin 1 and Mint 1 bind to the same site on the N-terminal CaM kinase domain of CASK and compete with each other for CASK binding. Our data suggest that in the vertebrate brain, CASK and Velis form alternative tripartite complexes with either Mint 1 or Caskin 1 that may couple CASK to distinct downstream effectors.
Embryonic neuronal death due to neurotrophin and neurotransmitter deprivation occurs independent of APAF-1 NEUROSCIENCE,106(2):263-274 2001 Author:N Honarpour; K Tabuchi; JM Stark; RE Hammer; TC Sudhof; LF Parada; Wang, X; JA Richardson; J Herz Abstract:Apoptotic protease-activating factor-1 (Apaf-1), dATP, and procaspase-9 form a multimeric complex that triggers programmed cell death through the activation of caspases upon release of cytochrome e from the mitochondria into the cytosol. Although cell death pathways exist that can bypass the requirement for cytochrome c release and caspase activation, several gene knockout studies have shown that the cytochrome c-mediated apoptotic pathway is critical for neural development. Specifically, the number of neuronal progenitor cells is abnormally increased in Apaf-1-, caspase-9-, caspase-3-deficient mice. However, the role of the cytochrome c cell death pathway for apoptosis of postmitotic, differentiated neurons in the developing brain has not been investigated in vivo. In this study we investigated embryonic neuronal cell death caused by trophic factor deprivation or lack of neurotransmitter release by analyzing Apaf-1/tyrosine kinase receptor A (TrkA) and Apaf-1/Munc-18 double mutant mice. Histological analysis of the double mutants' brains (including cell counting and terminal (TdT)-mediated dUTP-biotin nick end labeling (TUNEL) staining) reveals that neuronal cell death caused by these stimuli can proceed independent of Apaf-1.
We propose that a switch between apoptotic programs (and their respective proteins) characterizes the transition of a neuronal precursor cell from the progenitor pool to the postmitotic population of differentiated neurons. (C) 2001 IBRO. Published by Elsevier Science Ltd. All rights reserved.
Peroxiredoxin I expression in oral cancer: a potential new tumor marker CANCER LETTERS,156(1):27-35 2000(Aug.) Author:T Yanagawa; S Iwasa; T Ishii; K Tabuchi; H Yusa; K Onizawa; K Omura; H Harada; H Suzuki; H Yoshida Abstract:This study investigates the applicability of the novel antioxidant protein, peroxiredoxin (Prx) I as a marker for tumor status in oral squamous cell carcinoma (SCC). Samples from 53 patients with SCC in the oral cavity were examined by immunohistochemistry. Correlations between the expression level of Prx I and proliferating cell nuclear antigen (PCNA), the clinical features of tumors, and their histopathological classifications were statistically analyzed. Cases exhibiting low Prx I expression level included significantly more with larger tumor mass cases (T-category, P = 0.004), positive lymph node metastasis (N-category, P = 0.015), advanced stage (P = 0.002), and poorly differentiated cells (P = 0.020). There was no significant difference between Prx I expression and the other indices. (C) 2000 Published by Elsevier Science Ireland Ltd. All rights reserved.
c-Abl expression in oral squamous cell carcinomas ORAL ONCOLOGY,36(1):89-94 2000(Jan.) Author:T Yanagawa; H Harada; S Iwasa; K Tabuchi; K Omura; H Suzuki; H Yusa; K Yamagata; K Onizawa; T Ishii; H Yoshida Abstract:c-Abl is proto-oncogene product. c-Abl has roles in signal transduction, cell cycle regulation, and inhibition of apoptosis. There are many reports about c-Abl function in hematopoietic cells, but few are concerned with solid tumors. In the present study, biopsy specimens from 44 patients with oral squamous cell carcinomas were subjected to immunohistochemistry, and the expression levels of c-Abl were correlated with clinicopathological features. Statistical analyses revealed that c-Abl expression was significantly associated with T-category (p = 0.011), sex (p = 0.014), and differentiation (p = 0.007), but no significant difference was observed with N-category, age, primary tumor region, or the other histological gradings. The low c-Abl expression group included more T4, male, and poorly differentiated cases. There was a trend towards longer tendency survival in the high expression group, but the difference was not significant. We conclude that c-Abl is a good candidate for a tumor-expansion marker. (C) 2000 Elsevier Science Ltd. All rights reserved.
GAL4/UAS-WGA system as a powerful tool for tracing Drosophila transsynaptic neural pathways JOURNAL OF NEUROSCIENCE RESEARCH,59(1):94-99 2000(Jan.) Author:K Tabuchi; K Sawamoto; E Suzuki; K Ozaki; M Sone; C Hama; T Tanifuji-Morimoto; Y Yuasa; Y Yoshihara; A Nose; H Okano Abstract:Visualization of specific transsynaptic neural pathways is an indispensable technique for understanding the relationship between structure and function in the nervous system. Here, we demonstrate the application of the wheat germ agglutinin (WGA) transgene technique for tracing transsynaptic neural pathways in Drosophila. The intracellular localization of WGA was examined by immunoelectron microscopy. WGA signals were detected in granule-like structures in both the outer photoreceptor cells expressing WGA and the second-order laminar neurons. Misexpression of tetanus toxin (TNT), which inactivates N-synaptobrevin, in the outer photoreceptor cells resulted in the elimination of on/off transients in electroretinogram (ERG) recordings and in a great reduction in WGA transfer into laminar neurons, suggesting that anterograde WGA transsynaptic transfer is dependent mainly on synaptic transmission. Retrograde WGA transfer was also detected upon its forced expression in muscle cells. WGA primarily expressed in muscle cells was taken up by motoneuron axons and transported to their cell bodies in the ventral nerve cord, suggesting that WGA can trace motoneuronal pathways in combination with the muscle-specific GAL4 driver. Thus, the GAL4/UAS-WGA system should facilitate the dissection of the Drosophila neural circuit formation and/or synaptic activity in various regions and at various developmental stages. (C) 2000 Wiley-Liss, Inc.
Peroxiredoxin I expression in human thyroid tumors CANCER LETTERS,145(1-2):127-132 1999(Oct.) Author:T Yanagawa; T Ishikawa; T Ishii; K Tabuchi; S Iwasa; S Bannai; K Omura; H Suzuki; H Yoshida Abstract:Peroxiredoxin I (Prx I) is newly discovered oxidative stress inducible protein, having a thioredoxin peroxidase activity. The Prx I expression level in 107 samples out of 60 thyroid lesions, including normal thyroid, tumors and thyroiditis including Graves' disease were examined using immunoblotting. Prx I expression levels in follicular neoplasm (P = 0.00005) and thyroiditis group (P = 0.0037) were significantly higher than that of the control group, while papillary carcinoma group did not show statistical significance, Immunohistochemistry indicated that Pn; I was in epithelial cells of thyroid follicles. These results suggest that Prx I is expected to be a candidate for novel tumor markers to discriminate tissue types of tumors. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved.
Heme oxygenase-1 expression in oral squamous cell carcinoma as involved in lymph node metastasis CANCER LETTERS,138(1-2):53-59 1999(Apr.) Author:MH Tsuji; T Yanagawa; S Iwasa; K Tabuchi; K Onizawa; S Bannai; H Toyooka; H Yoshida Abstract:Thirty-eight oral squamous cell carcinomas (SCCs) were semi-quantitatively analyzed by immunohistochemical staining, and the relation between heme oxygenase-1 (HO-1) expression and the clinical status were correlated. High immunostaining of HO-1 was detected in lymph node metastasis negative groups (P = 0.0018) and in well-differentiated SCCs (P = 0.0016). There were no significant correlations between heme oxygenase-1 expression and other factors, such as size of the tumor, staging, age and sex. These findings further support the proposition that high heme oxygenase-1 expression in oral SCCs can be useful in identifying patients at low risk of lymph node metastasis. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved.
A genetic approach to visualization of multisynaptic neural pathways using plant lectin transgene NEURON,22(1):33-41 1999(Jan.) Author:Y Yoshihara; T Mizuno; M Nakahira; M Kawasaki; Y Watanabe; H Kagamiyama; K Jishage; O Ueda; H Suzuki; K Tabuchi; K Sawamoto; H Okano; T Noda; K Mori Abstract:The wiring patterns among various types of neurons via specific synaptic connections are the basis of functional logic employed by the brain for information processing. This study introduces a powerful method of analyzing the neuronal connectivity patterns by delivering a tracer selectively to specific types of neurons while simultaneously transsynaptically labeling their target neurons. We developed a novel genetic approach introducing cDNA for a plant lectin, wheat germ agglutinin (WGA), as a transgene under the control of specific promoter elements. Using this method, we demonstrate three examples of visualization of specific transsynaptic neural pathways: the mouse cerebellar efferent pathways, the mouse olfactory pathways, and the Drosophila visual pathways. This strategy should greatly facilitate studies on the anatomical and functional organization of the developing and mature nervous system.
A novel Drosophila paired-like homeobox gene related to Caenorhabditis elegans unc-4 is expressed in subsets of postmitotic neurons and epidermal cells NEUROSCIENCE LETTERS,257(1):49-52 1998(Nov.) Author:K Tabuchi; S Yoshikawa; Y Yuasa; K Sawamoto; H Okano Abstract:We have isolated a novel Drosophila paired-like homeobox gene, DPHD-1. The homeodomain of DPHD-1 showed 85% amino-acid identity with that of the C. elegans Unc-4 protein. Whole-mount in situ hybridization of embryos and third-instar larvae revealed that the DPHD-1 mRNA is specifically localized in subsets of postmitotic neurons in the central nervous system (CNS) and in the developing epidermis with a segmentally repeated pattern. Double staining with a posterior compartment marker, an anti-Engrailed antibody, showed that DPHD-1 expressing neurons in the CNS were present in the posterior compartment, whereas DPHD-1 expression in the epidermis was restricted to the anterior compartment in each segment. This temporal and spatial expression pattern suggests that DPHD-1 may play a role in determining the distinct cell types in each segment. (C) 1998 Elsevier Science Ireland Ltd. All rights reserved.
Localization of 5-HT2A receptor in rat cerebral cortex and olfactory system revealed by immunohistochemistry using two antibodies raised in rabbit and chicken MOLECULAR BRAIN RESEARCH,54(2):199-211 1998(Mar.) Author:S Hamada; K Senzaki; K Hamaguchi-Hamada; K Tabuchi; H Yamamoto; T Yamamoto; S Yoshikawa; H Okano; N Okado Abstract:Serotonin 2A receptor (5-HT2A receptor) is widely distributed in the central nervous system, and has been suggested to be involved in a variety of behavioral conditions and neuropsychiatric disorders. Two polyclonal antibodies were raised against the N-terminus peptide of rat 5-HT2A receptor in chickens (5-HT2A-N) and a glutathione S-transferase fusion protein that contained the C-terminus of the mouse 5-HT2A receptor in rabbits (5-HT2A-C). Affinity-purified 5-HT2A-N and -C antibodies reacted strongly with a single band of 77-78 kDa in postsynaptic density proteins prepared from the rat cortex. The distribution pattern of immunoreactive structures in the rat brain was virtually the same for the two antibodies. The highest levels of immunoreactivity were observed in the olfactory bulb, neocortex, claustrum, piriform cortex, mamillary bodies, pontine nuclei, red nucleus and cranial motor nuclei. In the olfactory bulb, mitral cells were intensely labeled. In the neocortex, many immunoreactive neurons were found in layers II-VI. In layer IV of the neocortex, strong neuropil labeling was observed. In a double-labeling study using chicken 5-HT2A-N and rabbit anti-glial fibrillary acidic protein (GFAP) antibody, a considerable number of GFAP positive cells also showed 5-HT2A immunoreactivity. By using an immunoelectron microscopic technique, 5-HT2A receptor immunoreaction was shown to be localized just beneath the postsynaptic membrane thickening of asymmetric synapses. (C) 1998 Elsevier Science B.V.
講演・口頭発表等 Synapse maturation and autism : The role of synapse adhesion molecules JOURNAL OF PHYSIOLOGICAL SCIENCES 2013 Presenter:Tabuchi, Katsuhiko; Chang Wen Hsin; Nur Farehan; Asgar Mohamed; Thomas, Sudhof C; Shigemoto, Ryuichi Abstract:JOURNAL OF PHYSIOLOGICAL SCIENCES
Genetic Animal Models of Autism ANNALS OF NEUROLOGY 2010 Presenter:Blundell, Jacqueline; Blaiss, Cory A; Etherton, Mark R; Zhou, Jing; Kwon, Chang-Hyuk; Espinosa, Felipe; Tabuchi, Katsuhiko; Bolliger, Marc E; Parada, Luis F; Sudhof, Thomas C; Powell; Craig M Abstract:ANNALS OF NEUROLOGY
Genetic Animal Models of Autism: Molecular Mechanisms and Potential Therapeutics ANNALS OF NEUROLOGY 2009 Presenter:Blundell, Jacqueline; Blaiss, Cory; Tabuchi, Katsuhiko; Zhou, Jing; Kwon, Chang; Bolliger, Marc; Parada, Luis; Sudhof, Thomas C; Powell; Craig M Abstract:ANNALS OF NEUROLOGY
Analysis of neuroligin-3 knock-in mice relevant to autism spectrum disorders NEUROSCIENCE RESEARCH 2009 Presenter:Tabuchi, Katsuhiko; Etherton, Mark; Shigemoto, Ryuichi; Sudhof, Thomas Abstract:NEUROSCIENCE RESEARCH
Novel Genetic Animal Models of Autism: Molecular Mechanisms to Therapeutic Targets NEUROLOGY 2009 Presenter:Powell; Craig M; Blundell, Jacqueline; Tabuchi, Katsuhiko; Zhou, Jing; Kwon, Chang; Etherton, Mark; Hammer, Robert; Liu, Xinran; Parada, Luis; Sudhof, Thomas C Abstract:NEUROLOGY
Autism as synapsopathy: Animal models based on genetic mutations in trans-synaptic cell adhesion molecules ANNALS OF NEUROLOGY 2008 Presenter:Blundell, Jacqueline; Tabuchi, Katsuhiko; Bolliger, Marc; Brose, Nils; Sudhof, Thomas C; Powell; Craig M Abstract:ANNALS OF NEUROLOGY
Neuroligin deletion results in autism & mental retardation-related behavioral abnormalities ANNALS OF NEUROLOGY 2007 Presenter:Blundell, Jacqueline; Tabuchi, Katsuhiko; Bolliger, Marc; Brose, Nils; Sudhof, Thomas C; Powell; Craig M Abstract:ANNALS OF NEUROLOGY
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