|
|
中澤 敬信 (ナカザワ タカノブ) NAKAZAWA Takanobu 教授 |
論文 【 表示 ／ 非表示 】
-
Pathogenic POGZ mutation causes impaired cortical development and reversible autism-like phenotypes.
Kensuke Matsumura, Kaoru Seiriki, Shota Okada, Masashi Nagase, Shinya Ayabe, Ikuko Yamada, Tamio Furuse, Hirotoshi Shibuya, Yuka Yasuda, Hidenaga Yamamori, Michiko Fujimoto, Kazuki Nagayasu, Kana Yamamoto, Kohei Kitagawa, Hiroki Miura, Nanaka Gotoda-Nishimura, Hisato Igarashi, Misuzu Hayashida, Masayuki Baba, Momoka Kondo, Shigeru Hasebe, Kosei Ueshima, Atsushi Kasai, Yukio Ago, Atsuko Hayata-Takano, Norihito Shintani, Tokuichi Iguchi, Makoto Sato, Shun Yamaguchi, Masaru Tamura, Shigeharu Wakana, Atsushi Yoshiki, Ayako M Watabe, Hideyuki Okano, Kazuhiro Takuma, Ryota Hashimoto, Hitoshi Hashimoto, Takanobu Nakazawa
Nature communications 11 ( 1 ) 859 - 859 2020年02月 [査読有り]
研究論文（学術雑誌） 共著
Pogo transposable element derived with ZNF domain (POGZ) has been identified as one of the most recurrently de novo mutated genes in patients with neurodevelopmental disorders (NDDs), including autism spectrum disorder (ASD), intellectual disability and White-Sutton syndrome; however, the neurobiological basis behind these disorders remains unknown. Here, we show that POGZ regulates neuronal development and that ASD-related de novo mutations impair neuronal development in the developing mouse brain and induced pluripotent cell lines from an ASD patient. We also develop the first mouse model heterozygous for a de novo POGZ mutation identified in a patient with ASD, and we identify ASD-like abnormalities in the mice. Importantly, social deficits can be treated by compensatory inhibition of elevated cell excitability in the mice. Our results provide insight into how de novo mutations on high-confidence ASD genes lead to impaired mature cortical network function, which underlies the cellular pathogenesis of NDDs, including ASD.
-
(S)-norketamine and (2S,6S)-hydroxynorketamine exert potent antidepressant-like effects in a chronic corticosterone-induced mouse model of depression.
Rei Yokoyama, Momoko Higuchi, Wataru Tanabe, Shinji Tsukada, Megumi Naito, Takumi Yamaguchi, Lu Chen, Atsushi Kasai, Kaoru Seiriki, Takanobu Nakazawa, Shinsaku Nakagawa, Kenji Hashimoto, Hitoshi Hashimoto, Yukio Ago
Pharmacology, biochemistry, and behavior 191 172876 - 172876 2020年02月 [査読有り]
研究論文（学術雑誌） 共著
Clinical and preclinical studies have shown that the N-methyl-d-aspartate receptor antagonist ketamine exerts rapid and long-lasting antidepressant effects. Although ketamine metabolites might also have potential antidepressant properties, controversial results have been reported for (2R,6R)-hydroxynorketamine ((2R,6R)-HNK) in particular, and there is little information regarding the effects of other ketamine metabolites. Here we aimed to compare the effects of (R)-norketamine ((R)-NK), (S)-NK, (2R,6R)-HNK, and (2S,6S)-HNK in a mouse model of depression induced by chronic corticosterone (CORT) injection. None of the ketamine metabolites at doses up to 20 mg/kg showed antidepressant-like activity in naïve male C57BL6/J mice. Chronic CORT treatment increased immobility in the forced swim test and caused anhedonic-like behaviors in the female encounter test. A single administration of (S)-NK and (2S,6S)-HNK dose-dependently reduced the enhanced immobility at 30 min after injection in chronic CORT-treated mice, while (R)-NK or (2R,6R)-HNK did not. Additionally, (S)-NK and (2S,6S)-HNK, but not (R)-NK or (2R,6R)-HNK, improved chronic CORT-induced anhedonia at 24 h after the injection. These results suggest that (S)-ketamine metabolites (S)-NK and (2S,6S)-HNK have potent acute and sustained antidepressant effects in rodents.
-
Autism-associated protein kinase D2 regulates embryonic cortical neuron development.
Kensuke Matsumura, Masayuki Baba, Kazuki Nagayasu, Kana Yamamoto, Momoka Kondo, Kohei Kitagawa, Tomoya Takemoto, Kaoru Seiriki, Atsushi Kasai, Yukio Ago, Atsuko Hayata-Takano, Norihito Shintani, Toshihiko Kuriu, Tokuichi Iguchi, Makoto Sato, Kazuhiro Takuma, Ryota Hashimoto, Hitoshi Hashimoto, Takanobu Nakazawa
Biochemical and biophysical research communications 519 ( 3 ) 626 - 632 2019年11月 [査読有り]
研究論文（学術雑誌） 共著
Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder, characterized by impaired social interaction, repetitive behavior and restricted interests. Although the molecular etiology of ASD remains largely unknown, recent studies have suggested that de novo mutations are significantly involved in the risk of ASD. We and others recently identified spontaneous de novo mutations in PKD2, a protein kinase D family member, in sporadic ASD cases. However, the biological significance of the de novo PKD2 mutations and the role of PKD2 in brain development remain unclear. Here, we performed functional analysis of PKD2 in cortical neuron development using in utero electroporation. PKD2 is highly expressed in cortical neural stem cells in the developing cortex and regulates cortical neuron development, including the neuronal differentiation of neural stem cells and migration of newborn neurons. Importantly, we determined that the ASD-associated de novo mutations impair the kinase activity of PKD2, suggesting that the de novo PKD2 mutations can be a risk factor for the disease by loss of function of PKD2. Our current findings provide novel insight into the molecular and cellular pathogenesis of ASD.
-
Psychiatric-disorder-related behavioral phenotypes and cortical hyperactivity in a mouse model of 3q29 deletion syndrome.
Masayuki Baba, Kazumasa Yokoyama, Kaoru Seiriki, Yuichiro Naka, Kensuke Matsumura, Momoka Kondo, Kana Yamamoto, Misuzu Hayashida, Atsushi Kasai, Yukio Ago, Kazuki Nagayasu, Atsuko Hayata-Takano, Akinori Takahashi, Shun Yamaguchi, Daisuke Mori, Norio Ozaki, Tadashi Yamamoto, Kazuhiro Takuma, Ryota Hashimoto, Hitoshi Hashimoto, Takanobu Nakazawa
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 44 ( 12 ) 2125 - 2135 2019年11月 [査読有り]
研究論文（学術雑誌） 共著
3q29 microdeletion, a rare recurrent copy number variant (CNV), greatly confers an increased risk of psychiatric disorders, such as schizophrenia and autism spectrum disorder (ASD), as well as intellectual disability. However, disease-relevant cellular phenotypes of 3q29 deletion syndrome remain to be identified. To reveal the molecular and cellular etiology of 3q29 deletion syndrome, we generated a mouse model of human 3q29 deletion syndrome by chromosome engineering, which achieved construct validity. 3q29 deletion (Df/+) mice showed reduced body weight and brain volume and, more importantly, impaired social interaction and prepulse inhibition. Importantly, the schizophrenia-related impaired prepulse inhibition was reversed by administration of antipsychotics. These findings are reminiscent of the growth defects and neuropsychiatric behavioral phenotypes in patients with 3q29 deletion syndrome and exemplify that the mouse model achieves some part of face validity and predictive validity. Unbiased whole-brain imaging revealed that neuronal hyperactivation after a behavioral task was strikingly exaggerated in a restricted region of the cortex of Df/+ mice. We further elucidated the cellular phenotypes of neuronal hyperactivation and the reduction of parvalbumin expression in the cortex of Df/+ mice. Thus, the 3q29 mouse model provides invaluable insight into the disease-causative molecular and cellular pathology of psychiatric disorders.
-
Pituitary Adenylate Cyclase-Activating Polypeptide Modulates Dendritic Spine Maturation and Morphogenesis via MicroRNA-132 Upregulation.
Atsuko Hayata-Takano, Toshihiko Kamo, Harui Kijima, Kaoru Seiriki, Katsuya Ogata, Yukio Ago, Takanobu Nakazawa, Yusuke Shintani, Kosuke Higashino, Kazuki Nagayasu, Norihito Shintani, Atsushi Kasai, James A Waschek, Hitoshi Hashimoto
The Journal of neuroscience : the official journal of the Society for Neuroscience 39 ( 22 ) 4208 - 4220 2019年05月 [査読有り]
研究論文（学術雑誌） 共著
Alterations in pituitary adenylate cyclase-activating polypeptide (PACAP), a multifunctional neuropeptide, and its receptors have been identified as risk factors for certain psychiatric disorders, including schizophrenia. Increasing evidence from human genetic and animal model studies suggest an association between various psychiatric disorders and altered dendritic spine morphology. In the present study, we investigated the role of exogenous and endogenous PACAP in spine formation and maturation. PACAP modified the density and morphology of PSD-95-positive spines in primary cultured hippocampal neurons. Notably, PACAP increased the levels of microRNA (miR)-132 and decreased expression of corresponding miR-132 target genes and protein expression of p250GAP, a miR-132 effector known to be involved in spine morphology regulation. In corroboration, PSD-95-positive spines were reduced in PACAP-deficient (PACAP-/-) mice versus WT mice. Golgi staining of hippocampal CA1 neurons revealed a reduced spine densities and atypical morphologies in the male PACAP-/- mice. Furthermore, viral miR-132 overexpression reversed the reduction in hippocampal spinal density in the male PACAP-/- mice. These results indicate that PACAP signaling plays a critical role in spine morphogenesis possibly via miR-132. We suggest that dysfunction of PACAP signaling may contribute to the pathogenesis of neuropsychiatric disorders, at least partly through its effects on spine formation.SIGNIFICANCE STATEMENT Pituitary adenylate cyclase-activating polypeptide (PACAP) signaling dysfunction and dendritic spine morphology alterations have recently been suggested as important pathophysiological mechanisms underlying several psychiatric and neurological disorders. In this study, we investigated whether PACAP regulates dendritic spine morphogenesis. In a combination of pharmacological and viral gain- and loss-of-function approaches in vitro and in vivo experiments, we found PACAP to increase the size and density of dendritic spines via miR-132 upregulation. Together, our data suggest that a dysfunction of PACAP signaling may contribute to the pathogenesis of neuropsychiatric disorders, at least partly through abnormal spine formation.
科研費（文科省・学振）獲得実績 【 表示 ／ 非表示 】
-
社会行動制御に関わる神経細胞の単一細胞レベルの解析及びその活動操作の基盤技術開発
挑戦的萌芽研究
研究期間: 2020年10月 - 2022年03月 代表者: 中澤 敬信
-
大規模患者リソース及びiPS技術を用いた統合失調症の病態予測のバイオマーカー開発
基盤研究(B)
研究期間: 2018年07月 - 2021年03月 代表者: 橋本亮太
統合失調症は、遺伝的・環境的要因が複雑に絡み合う多因子疾患であることが知られている。また、発症は一般には思春期であり、発症前の幼少期、発症オンセット、発症後、その後、場合により、治療抵抗性化、治療抵抗性統合失調症治療薬であるクロザピン抵抗性化というステップを経ることが示唆されている。従って、患者の発症前・後の状態を一貫して解析することが重要であると考えている。本研究では、クロザピン抵抗性化まで進行した患者を選択し、患者iPS細胞を神経幹細胞、未成熟神経細胞、および成熟神経細胞に分化させ、それぞれの細胞における神経機能の異常を明らかにすることによって、発症前の幼少期、発症オンセット、発症後、その後の治療抵抗性化、さらにはクロザピン抵抗性化という各ステップの分子病態を明らかにすることを目的にしている。先行して研究を実施してきた治療抵抗性統合失調症の一卵性双生児患者例におけるクロザピン応答性の分子基盤の一端として細胞接着分子群や転写因子群を同定している。今年度は、一卵性双生児患者例で同定してきた分子病態の妥当性を別な患者サンプルで評価した。すでに樹立済みのクロザピン応答性不一致例患者のiPS神経細胞サンプルの発現解析を実施したところ、細胞接着分子群のみならず、一部の転写因子群についても一卵性双生児患者でみられた分子病態の再現性が見られた。また、iPS神経細胞で同定された発現量の違いが血球系細胞でも同様に観察される可能性を検討することを目的として、当該患者の血液サンプルから全RNAを調製するとともに、患者群の臨床データの解析を実施した。iPS細胞関連技術を用いた治療応答性に注目した統合失調症研究の報告例はほとんどなく、同定した分子病態をさらに解析することにより、新たな統合失調症の発症、病気の進行、悪化、治療応答性等の分子基盤が明らかになることが期待される。
その他競争的資金獲得実績 【 表示 ／ 非表示 】
-
分子病態に基づく自閉症の分類化のトランスレーショナル研究
提供機関: 民間財団等 武田科学振興財団ビジョナリーリサーチ助成 （ホップ）
研究期間： 2020年10月 - 2022年10月 代表者: 中澤 敬信
-
自閉症に高頻度に認めるPOGZ遺伝子変異に注目した自己と他者との社会的相互作用制御の分子基盤解明
提供機関: 旭硝子財団 旭硝子財団 研究助成金
研究期間： 2018年 - 2019年 代表者: 中澤 敬信
-
提供機関: 武田科学振興財団 武田科学振興財団 ビジョナリーリサーチ助成（スタート）
研究期間： 2017年 - 2019年 代表者: 中澤 敬信
-
自閉症に高頻度に認めるPOGZ遺伝子変異の患者神経細胞を用いた分子薬理学研究
提供機関: 公益財団法人薬理研究会 公益財団法人薬理研究会 研究助成金
研究期間： 2017年 - 2018年 代表者: 中澤 敬信
受託研究受入実績 【 表示 ／ 非表示 】
-
神経発達障害の病態解明を目指した革新的イメージングプラットフォーム
提供機関: 日本医療研究開発機構（AMED） 一般受託研究
研究期間： 2019年10月 - 2025年03月 代表者: 岡部繁男
-
治療抵抗性統合失調症に対する客観的診断法及び実用的治療プロトコールの開発
提供機関: 日本医療研究開発機構（AMED） 一般受託研究
研究期間： 2016年04月 - 2017年03月 代表者: 橋本亮太
担当経験のある授業科目 【 表示 ／ 非表示 】
-
大阪大学大学院薬学研究科 先端生命科学特別講義
-
大阪大学歯学部 分子薬理学演習
-
大阪大学歯学部 分子薬理学講義
-
大阪大学大学院歯学研究科 大学院PBLプログラム「最新癌科学」
-
大阪大学大学院薬学研究科 大学院講義 神経薬理学