Research ArticleNeuroscienceTherapeutics Open Access | 10.1172/jci.insight.182060

Soichiro Ohnami,1,2 Megumi Naito,3 Haruki Kawase,3 Momoko Higuchi,3 Shigeru Hasebe,4,5 Keiko Takasu,1 Ryo Kanemaru,6 Yuki Azuma,1 Rei Yokoyama,3,7 Takahiro Kochi,8 Eiji Imado,7,8 Takeru Tahara,9 Yaichiro Kotake,9 Satoshi Asano,7 Naoya Oishi,2,10 Kazuhiro Takuma,4,11 Hitoshi Hashimoto,3,11,12,13,14 Koichi Ogawa,1,2 Atsushi Nakamura,1,6 Hidekuni Yamakawa,1,2,15 and Yukio Ago3,7,16,17

1Laboratory for Drug Discovery and Disease Research, Shionogi & Co. Ltd., Toyonaka, Osaka, Japan.

2SK Project, Medical Innovation Center, Graduate School of Medicine, Kyoto University, Kyoto, Kyoto, Japan.

3Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, and

4Department of Pharmacology, Graduate School of Dentistry, Osaka University, Suita, Osaka, Japan.

5Department of Social Pharmacy, Faculty of Pharmaceutical Sciences, Setsunan University, Hirakata, Osaka, Japan.

6Shionogi TechnoAdvance Research Co. Ltd., Toyonaka, Osaka, Japan.

7Department of Cellular and Molecular Pharmacology,

8Department of Dental Anesthesiology, and

9Department of Neurochemistry and Environmental Health Sciences, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Hiroshima, Japan.

10Department of Psychiatry, Graduate School of Medicine, Kyoto University, Kyoto, Kyoto, Japan.

11Molecular Research Center for Children’s Mental Development, United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University, and University of Fukui, Suita, Osaka, Japan.

12Division of Bioscience, Institute for Datability Science,

13Open and Transdisciplinary Research Initiatives, and

14Department of Molecular Pharmaceutical Sciences, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.

15Ping An-Shionogi Co. Ltd., Xuhui District, Shanghai, China.

16Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, and

17Global Center for Medical Engineering and Informatics, Osaka University, Suita, Osaka, Japan.

Address correspondence to: Hidekuni Yamakawa, Room 602, 6F, 199 Kaibin Road, Xuhui District, Shanghai, 200232, China. Phone: 86.139.1650.0142; Email: hidekuni.yamakawa@pingan-shionogi.com. Or to: Yukio Ago, 1-2-3 Kasumi, Minami-ku, Hiroshima, Hiroshima 734-8553, Japan. Phone: 81.82.257.5640; Email: yukioago@hiroshima-u.ac.jp.

Authorship note: SO and MN contributed equally to this work and are co–first authors.

Find articles by Ohnami, S. in: JCI | PubMed | Google Scholar

1Laboratory for Drug Discovery and Disease Research, Shionogi & Co. Ltd., Toyonaka, Osaka, Japan.

2SK Project, Medical Innovation Center, Graduate School of Medicine, Kyoto University, Kyoto, Kyoto, Japan.

3Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, and

4Department of Pharmacology, Graduate School of Dentistry, Osaka University, Suita, Osaka, Japan.

5Department of Social Pharmacy, Faculty of Pharmaceutical Sciences, Setsunan University, Hirakata, Osaka, Japan.

6Shionogi TechnoAdvance Research Co. Ltd., Toyonaka, Osaka, Japan.

7Department of Cellular and Molecular Pharmacology,

8Department of Dental Anesthesiology, and

9Department of Neurochemistry and Environmental Health Sciences, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Hiroshima, Japan.

10Department of Psychiatry, Graduate School of Medicine, Kyoto University, Kyoto, Kyoto, Japan.

11Molecular Research Center for Children’s Mental Development, United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University, and University of Fukui, Suita, Osaka, Japan.

12Division of Bioscience, Institute for Datability Science,

13Open and Transdisciplinary Research Initiatives, and

14Department of Molecular Pharmaceutical Sciences, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.

15Ping An-Shionogi Co. Ltd., Xuhui District, Shanghai, China.

16Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, and

17Global Center for Medical Engineering and Informatics, Osaka University, Suita, Osaka, Japan.

Address correspondence to: Hidekuni Yamakawa, Room 602, 6F, 199 Kaibin Road, Xuhui District, Shanghai, 200232, China. Phone: 86.139.1650.0142; Email: hidekuni.yamakawa@pingan-shionogi.com. Or to: Yukio Ago, 1-2-3 Kasumi, Minami-ku, Hiroshima, Hiroshima 734-8553, Japan. Phone: 81.82.257.5640; Email: yukioago@hiroshima-u.ac.jp.

Authorship note: SO and MN contributed equally to this work and are co–first authors.

Find articles by Naito, M. in: JCI | PubMed | Google Scholar

1Laboratory for Drug Discovery and Disease Research, Shionogi & Co. Ltd., Toyonaka, Osaka, Japan.

2SK Project, Medical Innovation Center, Graduate School of Medicine, Kyoto University, Kyoto, Kyoto, Japan.

3Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, and

4Department of Pharmacology, Graduate School of Dentistry, Osaka University, Suita, Osaka, Japan.

5Department of Social Pharmacy, Faculty of Pharmaceutical Sciences, Setsunan University, Hirakata, Osaka, Japan.

6Shionogi TechnoAdvance Research Co. Ltd., Toyonaka, Osaka, Japan.

7Department of Cellular and Molecular Pharmacology,

8Department of Dental Anesthesiology, and

9Department of Neurochemistry and Environmental Health Sciences, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Hiroshima, Japan.

10Department of Psychiatry, Graduate School of Medicine, Kyoto University, Kyoto, Kyoto, Japan.

11Molecular Research Center for Children’s Mental Development, United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University, and University of Fukui, Suita, Osaka, Japan.

12Division of Bioscience, Institute for Datability Science,

13Open and Transdisciplinary Research Initiatives, and

14Department of Molecular Pharmaceutical Sciences, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.

15Ping An-Shionogi Co. Ltd., Xuhui District, Shanghai, China.

16Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, and

17Global Center for Medical Engineering and Informatics, Osaka University, Suita, Osaka, Japan.

Address correspondence to: Hidekuni Yamakawa, Room 602, 6F, 199 Kaibin Road, Xuhui District, Shanghai, 200232, China. Phone: 86.139.1650.0142; Email: hidekuni.yamakawa@pingan-shionogi.com. Or to: Yukio Ago, 1-2-3 Kasumi, Minami-ku, Hiroshima, Hiroshima 734-8553, Japan. Phone: 81.82.257.5640; Email: yukioago@hiroshima-u.ac.jp.

Authorship note: SO and MN contributed equally to this work and are co–first authors.

Find articles by Kawase, H. in: JCI | PubMed | Google Scholar

1Laboratory for Drug Discovery and Disease Research, Shionogi & Co. Ltd., Toyonaka, Osaka, Japan.

2SK Project, Medical Innovation Center, Graduate School of Medicine, Kyoto University, Kyoto, Kyoto, Japan.

3Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, and

4Department of Pharmacology, Graduate School of Dentistry, Osaka University, Suita, Osaka, Japan.

5Department of Social Pharmacy, Faculty of Pharmaceutical Sciences, Setsunan University, Hirakata, Osaka, Japan.

6Shionogi TechnoAdvance Research Co. Ltd., Toyonaka, Osaka, Japan.

7Department of Cellular and Molecular Pharmacology,

8Department of Dental Anesthesiology, and

9Department of Neurochemistry and Environmental Health Sciences, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Hiroshima, Japan.

10Department of Psychiatry, Graduate School of Medicine, Kyoto University, Kyoto, Kyoto, Japan.

11Molecular Research Center for Children’s Mental Development, United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University, and University of Fukui, Suita, Osaka, Japan.

12Division of Bioscience, Institute for Datability Science,

13Open and Transdisciplinary Research Initiatives, and

14Department of Molecular Pharmaceutical Sciences, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.

15Ping An-Shionogi Co. Ltd., Xuhui District, Shanghai, China.

16Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, and

17Global Center for Medical Engineering and Informatics, Osaka University, Suita, Osaka, Japan.

Address correspondence to: Hidekuni Yamakawa, Room 602, 6F, 199 Kaibin Road, Xuhui District, Shanghai, 200232, China. Phone: 86.139.1650.0142; Email: hidekuni.yamakawa@pingan-shionogi.com. Or to: Yukio Ago, 1-2-3 Kasumi, Minami-ku, Hiroshima, Hiroshima 734-8553, Japan. Phone: 81.82.257.5640; Email: yukioago@hiroshima-u.ac.jp.

Authorship note: SO and MN contributed equally to this work and are co–first authors.

Find articles by Higuchi, M. in: JCI | PubMed | Google Scholar

1Laboratory for Drug Discovery and Disease Research, Shionogi & Co. Ltd., Toyonaka, Osaka, Japan.

2SK Project, Medical Innovation Center, Graduate School of Medicine, Kyoto University, Kyoto, Kyoto, Japan.

3Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, and

4Department of Pharmacology, Graduate School of Dentistry, Osaka University, Suita, Osaka, Japan.

5Department of Social Pharmacy, Faculty of Pharmaceutical Sciences, Setsunan University, Hirakata, Osaka, Japan.

6Shionogi TechnoAdvance Research Co. Ltd., Toyonaka, Osaka, Japan.

7Department of Cellular and Molecular Pharmacology,

8Department of Dental Anesthesiology, and

9Department of Neurochemistry and Environmental Health Sciences, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Hiroshima, Japan.

10Department of Psychiatry, Graduate School of Medicine, Kyoto University, Kyoto, Kyoto, Japan.

11Molecular Research Center for Children’s Mental Development, United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University, and University of Fukui, Suita, Osaka, Japan.

12Division of Bioscience, Institute for Datability Science,

13Open and Transdisciplinary Research Initiatives, and

14Department of Molecular Pharmaceutical Sciences, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.

15Ping An-Shionogi Co. Ltd., Xuhui District, Shanghai, China.

16Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, and

17Global Center for Medical Engineering and Informatics, Osaka University, Suita, Osaka, Japan.

Address correspondence to: Hidekuni Yamakawa, Room 602, 6F, 199 Kaibin Road, Xuhui District, Shanghai, 200232, China. Phone: 86.139.1650.0142; Email: hidekuni.yamakawa@pingan-shionogi.com. Or to: Yukio Ago, 1-2-3 Kasumi, Minami-ku, Hiroshima, Hiroshima 734-8553, Japan. Phone: 81.82.257.5640; Email: yukioago@hiroshima-u.ac.jp.

Authorship note: SO and MN contributed equally to this work and are co–first authors.

Find articles by Hasebe, S. in: JCI | PubMed | Google Scholar

1Laboratory for Drug Discovery and Disease Research, Shionogi & Co. Ltd., Toyonaka, Osaka, Japan.

2SK Project, Medical Innovation Center, Graduate School of Medicine, Kyoto University, Kyoto, Kyoto, Japan.

3Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, and

4Department of Pharmacology, Graduate School of Dentistry, Osaka University, Suita, Osaka, Japan.

5Department of Social Pharmacy, Faculty of Pharmaceutical Sciences, Setsunan University, Hirakata, Osaka, Japan.

6Shionogi TechnoAdvance Research Co. Ltd., Toyonaka, Osaka, Japan.

7Department of Cellular and Molecular Pharmacology,

8Department of Dental Anesthesiology, and

9Department of Neurochemistry and Environmental Health Sciences, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Hiroshima, Japan.

10Department of Psychiatry, Graduate School of Medicine, Kyoto University, Kyoto, Kyoto, Japan.

11Molecular Research Center for Children’s Mental Development, United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University, and University of Fukui, Suita, Osaka, Japan.

12Division of Bioscience, Institute for Datability Science,

13Open and Transdisciplinary Research Initiatives, and

14Department of Molecular Pharmaceutical Sciences, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.

15Ping An-Shionogi Co. Ltd., Xuhui District, Shanghai, China.

16Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, and

17Global Center for Medical Engineering and Informatics, Osaka University, Suita, Osaka, Japan.

Address correspondence to: Hidekuni Yamakawa, Room 602, 6F, 199 Kaibin Road, Xuhui District, Shanghai, 200232, China. Phone: 86.139.1650.0142; Email: hidekuni.yamakawa@pingan-shionogi.com. Or to: Yukio Ago, 1-2-3 Kasumi, Minami-ku, Hiroshima, Hiroshima 734-8553, Japan. Phone: 81.82.257.5640; Email: yukioago@hiroshima-u.ac.jp.

Authorship note: SO and MN contributed equally to this work and are co–first authors.

Find articles by Takasu, K. in: JCI | PubMed | Google Scholar

1Laboratory for Drug Discovery and Disease Research, Shionogi & Co. Ltd., Toyonaka, Osaka, Japan.

2SK Project, Medical Innovation Center, Graduate School of Medicine, Kyoto University, Kyoto, Kyoto, Japan.

3Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, and

4Department of Pharmacology, Graduate School of Dentistry, Osaka University, Suita, Osaka, Japan.

5Department of Social Pharmacy, Faculty of Pharmaceutical Sciences, Setsunan University, Hirakata, Osaka, Japan.

6Shionogi TechnoAdvance Research Co. Ltd., Toyonaka, Osaka, Japan.

7Department of Cellular and Molecular Pharmacology,

8Department of Dental Anesthesiology, and

9Department of Neurochemistry and Environmental Health Sciences, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Hiroshima, Japan.

10Department of Psychiatry, Graduate School of Medicine, Kyoto University, Kyoto, Kyoto, Japan.

11Molecular Research Center for Children’s Mental Development, United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University, and University of Fukui, Suita, Osaka, Japan.

12Division of Bioscience, Institute for Datability Science,

13Open and Transdisciplinary Research Initiatives, and

14Department of Molecular Pharmaceutical Sciences, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.

15Ping An-Shionogi Co. Ltd., Xuhui District, Shanghai, China.

16Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, and

17Global Center for Medical Engineering and Informatics, Osaka University, Suita, Osaka, Japan.

Address correspondence to: Hidekuni Yamakawa, Room 602, 6F, 199 Kaibin Road, Xuhui District, Shanghai, 200232, China. Phone: 86.139.1650.0142; Email: hidekuni.yamakawa@pingan-shionogi.com. Or to: Yukio Ago, 1-2-3 Kasumi, Minami-ku, Hiroshima, Hiroshima 734-8553, Japan. Phone: 81.82.257.5640; Email: yukioago@hiroshima-u.ac.jp.

Authorship note: SO and MN contributed equally to this work and are co–first authors.

Find articles by Kanemaru, R. in: JCI | PubMed | Google Scholar

1Laboratory for Drug Discovery and Disease Research, Shionogi & Co. Ltd., Toyonaka, Osaka, Japan.

2SK Project, Medical Innovation Center, Graduate School of Medicine, Kyoto University, Kyoto, Kyoto, Japan.

3Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, and

4Department of Pharmacology, Graduate School of Dentistry, Osaka University, Suita, Osaka, Japan.

5Department of Social Pharmacy, Faculty of Pharmaceutical Sciences, Setsunan University, Hirakata, Osaka, Japan.

6Shionogi TechnoAdvance Research Co. Ltd., Toyonaka, Osaka, Japan.

7Department of Cellular and Molecular Pharmacology,

8Department of Dental Anesthesiology, and

9Department of Neurochemistry and Environmental Health Sciences, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Hiroshima, Japan.

10Department of Psychiatry, Graduate School of Medicine, Kyoto University, Kyoto, Kyoto, Japan.

11Molecular Research Center for Children’s Mental Development, United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University, and University of Fukui, Suita, Osaka, Japan.

12Division of Bioscience, Institute for Datability Science,

13Open and Transdisciplinary Research Initiatives, and

14Department of Molecular Pharmaceutical Sciences, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.

15Ping An-Shionogi Co. Ltd., Xuhui District, Shanghai, China.

16Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, and

17Global Center for Medical Engineering and Informatics, Osaka University, Suita, Osaka, Japan.

Address correspondence to: Hidekuni Yamakawa, Room 602, 6F, 199 Kaibin Road, Xuhui District, Shanghai, 200232, China. Phone: 86.139.1650.0142; Email: hidekuni.yamakawa@pingan-shionogi.com. Or to: Yukio Ago, 1-2-3 Kasumi, Minami-ku, Hiroshima, Hiroshima 734-8553, Japan. Phone: 81.82.257.5640; Email: yukioago@hiroshima-u.ac.jp.

Authorship note: SO and MN contributed equally to this work and are co–first authors.

Find articles by Azuma, Y. in: JCI | PubMed | Google Scholar

1Laboratory for Drug Discovery and Disease Research, Shionogi & Co. Ltd., Toyonaka, Osaka, Japan.

2SK Project, Medical Innovation Center, Graduate School of Medicine, Kyoto University, Kyoto, Kyoto, Japan.

3Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, and

4Department of Pharmacology, Graduate School of Dentistry, Osaka University, Suita, Osaka, Japan.

5Department of Social Pharmacy, Faculty of Pharmaceutical Sciences, Setsunan University, Hirakata, Osaka, Japan.

6Shionogi TechnoAdvance Research Co. Ltd., Toyonaka, Osaka, Japan.

7Department of Cellular and Molecular Pharmacology,

8Department of Dental Anesthesiology, and

9Department of Neurochemistry and Environmental Health Sciences, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Hiroshima, Japan.

10Department of Psychiatry, Graduate School of Medicine, Kyoto University, Kyoto, Kyoto, Japan.

11Molecular Research Center for Children’s Mental Development, United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University, and University of Fukui, Suita, Osaka, Japan.

12Division of Bioscience, Institute for Datability Science,

13Open and Transdisciplinary Research Initiatives, and

14Department of Molecular Pharmaceutical Sciences, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.

15Ping An-Shionogi Co. Ltd., Xuhui District, Shanghai, China.

16Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, and

17Global Center for Medical Engineering and Informatics, Osaka University, Suita, Osaka, Japan.

Address correspondence to: Hidekuni Yamakawa, Room 602, 6F, 199 Kaibin Road, Xuhui District, Shanghai, 200232, China. Phone: 86.139.1650.0142; Email: hidekuni.yamakawa@pingan-shionogi.com. Or to: Yukio Ago, 1-2-3 Kasumi, Minami-ku, Hiroshima, Hiroshima 734-8553, Japan. Phone: 81.82.257.5640; Email: yukioago@hiroshima-u.ac.jp.

Authorship note: SO and MN contributed equally to this work and are co–first authors.

Find articles by Yokoyama, R. in: JCI | PubMed | Google Scholar

1Laboratory for Drug Discovery and Disease Research, Shionogi & Co. Ltd., Toyonaka, Osaka, Japan.

2SK Project, Medical Innovation Center, Graduate School of Medicine, Kyoto University, Kyoto, Kyoto, Japan.

3Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, and

4Department of Pharmacology, Graduate School of Dentistry, Osaka University, Suita, Osaka, Japan.

5Department of Social Pharmacy, Faculty of Pharmaceutical Sciences, Setsunan University, Hirakata, Osaka, Japan.

6Shionogi TechnoAdvance Research Co. Ltd., Toyonaka, Osaka, Japan.

7Department of Cellular and Molecular Pharmacology,

8Department of Dental Anesthesiology, and

9Department of Neurochemistry and Environmental Health Sciences, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Hiroshima, Japan.

10Department of Psychiatry, Graduate School of Medicine, Kyoto University, Kyoto, Kyoto, Japan.

11Molecular Research Center for Children’s Mental Development, United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University, and University of Fukui, Suita, Osaka, Japan.

12Division of Bioscience, Institute for Datability Science,

13Open and Transdisciplinary Research Initiatives, and

14Department of Molecular Pharmaceutical Sciences, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.

15Ping An-Shionogi Co. Ltd., Xuhui District, Shanghai, China.

16Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, and

17Global Center for Medical Engineering and Informatics, Osaka University, Suita, Osaka, Japan.

Address correspondence to: Hidekuni Yamakawa, Room 602, 6F, 199 Kaibin Road, Xuhui District, Shanghai, 200232, China. Phone: 86.139.1650.0142; Email: hidekuni.yamakawa@pingan-shionogi.com. Or to: Yukio Ago, 1-2-3 Kasumi, Minami-ku, Hiroshima, Hiroshima 734-8553, Japan. Phone: 81.82.257.5640; Email: yukioago@hiroshima-u.ac.jp.

Authorship note: SO and MN contributed equally to this work and are co–first authors.

Find articles by Kochi, T. in: JCI | PubMed | Google Scholar

1Laboratory for Drug Discovery and Disease Research, Shionogi & Co. Ltd., Toyonaka, Osaka, Japan.

2SK Project, Medical Innovation Center, Graduate School of Medicine, Kyoto University, Kyoto, Kyoto, Japan.

3Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, and

4Department of Pharmacology, Graduate School of Dentistry, Osaka University, Suita, Osaka, Japan.

5Department of Social Pharmacy, Faculty of Pharmaceutical Sciences, Setsunan University, Hirakata, Osaka, Japan.

6Shionogi TechnoAdvance Research Co. Ltd., Toyonaka, Osaka, Japan.

7Department of Cellular and Molecular Pharmacology,

8Department of Dental Anesthesiology, and

9Department of Neurochemistry and Environmental Health Sciences, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Hiroshima, Japan.

10Department of Psychiatry, Graduate School of Medicine, Kyoto University, Kyoto, Kyoto, Japan.

11Molecular Research Center for Children’s Mental Development, United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University, and University of Fukui, Suita, Osaka, Japan.

12Division of Bioscience, Institute for Datability Science,

13Open and Transdisciplinary Research Initiatives, and

14Department of Molecular Pharmaceutical Sciences, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.

15Ping An-Shionogi Co. Ltd., Xuhui District, Shanghai, China.

16Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, and

17Global Center for Medical Engineering and Informatics, Osaka University, Suita, Osaka, Japan.

Address correspondence to: Hidekuni Yamakawa, Room 602, 6F, 199 Kaibin Road, Xuhui District, Shanghai, 200232, China. Phone: 86.139.1650.0142; Email: hidekuni.yamakawa@pingan-shionogi.com. Or to: Yukio Ago, 1-2-3 Kasumi, Minami-ku, Hiroshima, Hiroshima 734-8553, Japan. Phone: 81.82.257.5640; Email: yukioago@hiroshima-u.ac.jp.

Authorship note: SO and MN contributed equally to this work and are co–first authors.

Find articles by Imado, E. in: JCI | PubMed | Google Scholar

1Laboratory for Drug Discovery and Disease Research, Shionogi & Co. Ltd., Toyonaka, Osaka, Japan.

2SK Project, Medical Innovation Center, Graduate School of Medicine, Kyoto University, Kyoto, Kyoto, Japan.

3Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, and

4Department of Pharmacology, Graduate School of Dentistry, Osaka University, Suita, Osaka, Japan.

5Department of Social Pharmacy, Faculty of Pharmaceutical Sciences, Setsunan University, Hirakata, Osaka, Japan.

6Shionogi TechnoAdvance Research Co. Ltd., Toyonaka, Osaka, Japan.

7Department of Cellular and Molecular Pharmacology,

8Department of Dental Anesthesiology, and

9Department of Neurochemistry and Environmental Health Sciences, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Hiroshima, Japan.

10Department of Psychiatry, Graduate School of Medicine, Kyoto University, Kyoto, Kyoto, Japan.

11Molecular Research Center for Children’s Mental Development, United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University, and University of Fukui, Suita, Osaka, Japan.

12Division of Bioscience, Institute for Datability Science,

13Open and Transdisciplinary Research Initiatives, and

14Department of Molecular Pharmaceutical Sciences, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.

15Ping An-Shionogi Co. Ltd., Xuhui District, Shanghai, China.

16Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, and

17Global Center for Medical Engineering and Informatics, Osaka University, Suita, Osaka, Japan.

Address correspondence to: Hidekuni Yamakawa, Room 602, 6F, 199 Kaibin Road, Xuhui District, Shanghai, 200232, China. Phone: 86.139.1650.0142; Email: hidekuni.yamakawa@pingan-shionogi.com. Or to: Yukio Ago, 1-2-3 Kasumi, Minami-ku, Hiroshima, Hiroshima 734-8553, Japan. Phone: 81.82.257.5640; Email: yukioago@hiroshima-u.ac.jp.

Authorship note: SO and MN contributed equally to this work and are co–first authors.

Find articles by Tahara, T. in: JCI | PubMed | Google Scholar

1Laboratory for Drug Discovery and Disease Research, Shionogi & Co. Ltd., Toyonaka, Osaka, Japan.

2SK Project, Medical Innovation Center, Graduate School of Medicine, Kyoto University, Kyoto, Kyoto, Japan.

3Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, and

4Department of Pharmacology, Graduate School of Dentistry, Osaka University, Suita, Osaka, Japan.

5Department of Social Pharmacy, Faculty of Pharmaceutical Sciences, Setsunan University, Hirakata, Osaka, Japan.

6Shionogi TechnoAdvance Research Co. Ltd., Toyonaka, Osaka, Japan.

7Department of Cellular and Molecular Pharmacology,

8Department of Dental Anesthesiology, and

9Department of Neurochemistry and Environmental Health Sciences, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Hiroshima, Japan.

10Department of Psychiatry, Graduate School of Medicine, Kyoto University, Kyoto, Kyoto, Japan.

11Molecular Research Center for Children’s Mental Development, United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University, and University of Fukui, Suita, Osaka, Japan.

12Division of Bioscience, Institute for Datability Science,

13Open and Transdisciplinary Research Initiatives, and

14Department of Molecular Pharmaceutical Sciences, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.

15Ping An-Shionogi Co. Ltd., Xuhui District, Shanghai, China.

16Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, and

17Global Center for Medical Engineering and Informatics, Osaka University, Suita, Osaka, Japan.

Address correspondence to: Hidekuni Yamakawa, Room 602, 6F, 199 Kaibin Road, Xuhui District, Shanghai, 200232, China. Phone: 86.139.1650.0142; Email: hidekuni.yamakawa@pingan-shionogi.com. Or to: Yukio Ago, 1-2-3 Kasumi, Minami-ku, Hiroshima, Hiroshima 734-8553, Japan. Phone: 81.82.257.5640; Email: yukioago@hiroshima-u.ac.jp.

Authorship note: SO and MN contributed equally to this work and are co–first authors.

Find articles by Kotake, Y. in: JCI | PubMed | Google Scholar

1Laboratory for Drug Discovery and Disease Research, Shionogi & Co. Ltd., Toyonaka, Osaka, Japan.

2SK Project, Medical Innovation Center, Graduate School of Medicine, Kyoto University, Kyoto, Kyoto, Japan.

3Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, and

4Department of Pharmacology, Graduate School of Dentistry, Osaka University, Suita, Osaka, Japan.

5Department of Social Pharmacy, Faculty of Pharmaceutical Sciences, Setsunan University, Hirakata, Osaka, Japan.

6Shionogi TechnoAdvance Research Co. Ltd., Toyonaka, Osaka, Japan.

7Department of Cellular and Molecular Pharmacology,

8Department of Dental Anesthesiology, and

9Department of Neurochemistry and Environmental Health Sciences, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Hiroshima, Japan.

10Department of Psychiatry, Graduate School of Medicine, Kyoto University, Kyoto, Kyoto, Japan.

11Molecular Research Center for Children’s Mental Development, United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University, and University of Fukui, Suita, Osaka, Japan.

12Division of Bioscience, Institute for Datability Science,

13Open and Transdisciplinary Research Initiatives, and

14Department of Molecular Pharmaceutical Sciences, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.

15Ping An-Shionogi Co. Ltd., Xuhui District, Shanghai, China.

16Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, and

17Global Center for Medical Engineering and Informatics, Osaka University, Suita, Osaka, Japan.

Address correspondence to: Hidekuni Yamakawa, Room 602, 6F, 199 Kaibin Road, Xuhui District, Shanghai, 200232, China. Phone: 86.139.1650.0142; Email: hidekuni.yamakawa@pingan-shionogi.com. Or to: Yukio Ago, 1-2-3 Kasumi, Minami-ku, Hiroshima, Hiroshima 734-8553, Japan. Phone: 81.82.257.5640; Email: yukioago@hiroshima-u.ac.jp.

Authorship note: SO and MN contributed equally to this work and are co–first authors.

Find articles by Asano, S. in: JCI | PubMed | Google Scholar

1Laboratory for Drug Discovery and Disease Research, Shionogi & Co. Ltd., Toyonaka, Osaka, Japan.

2SK Project, Medical Innovation Center, Graduate School of Medicine, Kyoto University, Kyoto, Kyoto, Japan.

3Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, and

4Department of Pharmacology, Graduate School of Dentistry, Osaka University, Suita, Osaka, Japan.

5Department of Social Pharmacy, Faculty of Pharmaceutical Sciences, Setsunan University, Hirakata, Osaka, Japan.

6Shionogi TechnoAdvance Research Co. Ltd., Toyonaka, Osaka, Japan.

7Department of Cellular and Molecular Pharmacology,

8Department of Dental Anesthesiology, and

9Department of Neurochemistry and Environmental Health Sciences, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Hiroshima, Japan.

10Department of Psychiatry, Graduate School of Medicine, Kyoto University, Kyoto, Kyoto, Japan.

11Molecular Research Center for Children’s Mental Development, United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University, and University of Fukui, Suita, Osaka, Japan.

12Division of Bioscience, Institute for Datability Science,

13Open and Transdisciplinary Research Initiatives, and

14Department of Molecular Pharmaceutical Sciences, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.

15Ping An-Shionogi Co. Ltd., Xuhui District, Shanghai, China.

16Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, and

17Global Center for Medical Engineering and Informatics, Osaka University, Suita, Osaka, Japan.

Address correspondence to: Hidekuni Yamakawa, Room 602, 6F, 199 Kaibin Road, Xuhui District, Shanghai, 200232, China. Phone: 86.139.1650.0142; Email: hidekuni.yamakawa@pingan-shionogi.com. Or to: Yukio Ago, 1-2-3 Kasumi, Minami-ku, Hiroshima, Hiroshima 734-8553, Japan. Phone: 81.82.257.5640; Email: yukioago@hiroshima-u.ac.jp.

Authorship note: SO and MN contributed equally to this work and are co–first authors.

Find articles by Oishi, N. in: JCI | PubMed | Google Scholar

1Laboratory for Drug Discovery and Disease Research, Shionogi & Co. Ltd., Toyonaka, Osaka, Japan.

2SK Project, Medical Innovation Center, Graduate School of Medicine, Kyoto University, Kyoto, Kyoto, Japan.

3Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, and

4Department of Pharmacology, Graduate School of Dentistry, Osaka University, Suita, Osaka, Japan.

5Department of Social Pharmacy, Faculty of Pharmaceutical Sciences, Setsunan University, Hirakata, Osaka, Japan.

6Shionogi TechnoAdvance Research Co. Ltd., Toyonaka, Osaka, Japan.

7Department of Cellular and Molecular Pharmacology,

8Department of Dental Anesthesiology, and

9Department of Neurochemistry and Environmental Health Sciences, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Hiroshima, Japan.

10Department of Psychiatry, Graduate School of Medicine, Kyoto University, Kyoto, Kyoto, Japan.

11Molecular Research Center for Children’s Mental Development, United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University, and University of Fukui, Suita, Osaka, Japan.

12Division of Bioscience, Institute for Datability Science,

13Open and Transdisciplinary Research Initiatives, and

14Department of Molecular Pharmaceutical Sciences, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.

15Ping An-Shionogi Co. Ltd., Xuhui District, Shanghai, China.

16Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, and

17Global Center for Medical Engineering and Informatics, Osaka University, Suita, Osaka, Japan.

Address correspondence to: Hidekuni Yamakawa, Room 602, 6F, 199 Kaibin Road, Xuhui District, Shanghai, 200232, China. Phone: 86.139.1650.0142; Email: hidekuni.yamakawa@pingan-shionogi.com. Or to: Yukio Ago, 1-2-3 Kasumi, Minami-ku, Hiroshima, Hiroshima 734-8553, Japan. Phone: 81.82.257.5640; Email: yukioago@hiroshima-u.ac.jp.

Authorship note: SO and MN contributed equally to this work and are co–first authors.

Find articles by Takuma, K. in: JCI | PubMed | Google Scholar

1Laboratory for Drug Discovery and Disease Research, Shionogi & Co. Ltd., Toyonaka, Osaka, Japan.

2SK Project, Medical Innovation Center, Graduate School of Medicine, Kyoto University, Kyoto, Kyoto, Japan.

3Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, and

4Department of Pharmacology, Graduate School of Dentistry, Osaka University, Suita, Osaka, Japan.

5Department of Social Pharmacy, Faculty of Pharmaceutical Sciences, Setsunan University, Hirakata, Osaka, Japan.

6Shionogi TechnoAdvance Research Co. Ltd., Toyonaka, Osaka, Japan.

7Department of Cellular and Molecular Pharmacology,

8Department of Dental Anesthesiology, and

9Department of Neurochemistry and Environmental Health Sciences, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Hiroshima, Japan.

10Department of Psychiatry, Graduate School of Medicine, Kyoto University, Kyoto, Kyoto, Japan.

11Molecular Research Center for Children’s Mental Development, United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University, and University of Fukui, Suita, Osaka, Japan.

12Division of Bioscience, Institute for Datability Science,

13Open and Transdisciplinary Research Initiatives, and

14Department of Molecular Pharmaceutical Sciences, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.

15Ping An-Shionogi Co. Ltd., Xuhui District, Shanghai, China.

16Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, and

17Global Center for Medical Engineering and Informatics, Osaka University, Suita, Osaka, Japan.

Address correspondence to: Hidekuni Yamakawa, Room 602, 6F, 199 Kaibin Road, Xuhui District, Shanghai, 200232, China. Phone: 86.139.1650.0142; Email: hidekuni.yamakawa@pingan-shionogi.com. Or to: Yukio Ago, 1-2-3 Kasumi, Minami-ku, Hiroshima, Hiroshima 734-8553, Japan. Phone: 81.82.257.5640; Email: yukioago@hiroshima-u.ac.jp.

Authorship note: SO and MN contributed equally to this work and are co–first authors.

Find articles by Hashimoto, H. in: JCI | PubMed | Google Scholar |

1Laboratory for Drug Discovery and Disease Research, Shionogi & Co. Ltd., Toyonaka, Osaka, Japan.

2SK Project, Medical Innovation Center, Graduate School of Medicine, Kyoto University, Kyoto, Kyoto, Japan.

3Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, and

4Department of Pharmacology, Graduate School of Dentistry, Osaka University, Suita, Osaka, Japan.

5Department of Social Pharmacy, Faculty of Pharmaceutical Sciences, Setsunan University, Hirakata, Osaka, Japan.

6Shionogi TechnoAdvance Research Co. Ltd., Toyonaka, Osaka, Japan.

7Department of Cellular and Molecular Pharmacology,

8Department of Dental Anesthesiology, and

9Department of Neurochemistry and Environmental Health Sciences, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Hiroshima, Japan.

10Department of Psychiatry, Graduate School of Medicine, Kyoto University, Kyoto, Kyoto, Japan.

11Molecular Research Center for Children’s Mental Development, United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University, and University of Fukui, Suita, Osaka, Japan.

12Division of Bioscience, Institute for Datability Science,

13Open and Transdisciplinary Research Initiatives, and