Large-scale animal model study uncovers altered brain pH and lactate levels as a transdiagnostic endophenotype of neuropsychiatric disorders involving cognitive impairment-Reference-Cited by-同舟云学术

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

Published:2023-12-28 Issue: Volume: Page:
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Hagihara Hideo¹^ORCID,Shoji Hirotaka¹^ORCID,Hattori Satoko¹^ORCID,Sala Giovanni¹,Takamiya Yoshihiro¹,Tanaka Mika¹,Ihara Masafumi²^ORCID,Shibutani Mihiro³,Hatada Izuho³,Hori Kei⁴,Hoshino Mikio⁴,Nakao Akito⁵^ORCID,Mori Yasuo⁵,Okabe Shigeo⁶^ORCID,Matsushita Masayuki⁷,Urbach Anja⁸^ORCID,Katayama Yuta⁹,Matsumoto Akinobu⁹,Nakayama Keiichi I.⁹^ORCID,Katori Shota¹⁰,Sato Takuya¹⁰^ORCID,Iwasato Takuji¹⁰,Nakamura Haruko¹¹,Goshima Yoshio¹¹^ORCID,Raveau Matthieu¹²,Tatsukawa Tetsuya¹²^ORCID,Yamakawa Kazuhiro¹²¹³^ORCID,Takahashi Noriko¹⁴¹⁵^ORCID,Kasai Haruo¹⁴¹⁶^ORCID,Inazawa Johji¹⁷^ORCID,Nobuhisa Ikuo¹⁸,Kagawa Tetsushi¹⁸,Taga Tetsuya¹⁸,Darwish Mohamed¹⁹²⁰,Nishizono Hirofumi²¹^ORCID,Takao Keizo²⁰²²^ORCID,Sapkota Kiran²³^ORCID,Nakazawa Kazutoshi²³^ORCID,Takagi Tsuyoshi²⁴,Fujisawa Haruki²⁵,Sugimura Yoshihisa²⁵,Yamanishi Kyosuke²⁶,Rajagopal Lakshmi²⁷^ORCID,Hannah Nanette Deneen²⁷,Meltzer Herbert Y.²⁷^ORCID,Yamamoto Tohru²⁸^ORCID,Wakatsuki Shuji²⁹^ORCID,Araki Toshiyuki²⁹^ORCID,Tabuchi Katsuhiko³⁰^ORCID,Numakawa Tadahiro³¹,Kunugi Hiroshi³¹³²^ORCID,Huang Freesia L.³³,Hayata-Takano Atsuko³⁴³⁵³⁶^ORCID,Hashimoto Hitoshi³⁴³⁶³⁷³⁸³⁹^ORCID,Tamada Kota⁴⁰⁴¹,Takumi Toru⁴⁰⁴¹^ORCID,Kasahara Takaoki⁴²⁴³^ORCID,Kato Tadafumi⁴²⁴⁴^ORCID,Graef Isabella A.⁴⁵,Crabtree Gerald R.⁴⁵,Asaoka Nozomi⁴⁶^ORCID,Hatakama Hikari⁴⁷,Kaneko Shuji⁴⁷^ORCID,Kohno Takao⁴⁸^ORCID,Hattori Mitsuharu⁴⁸^ORCID,Hoshiba Yoshio⁴⁹,Miyake Ryuhei⁵⁰,Obi-Nagata Kisho⁵⁰,Hayashi-Takagi Akiko⁴⁹⁵⁰,Becker Léa J.⁵¹,Yalcin Ipek⁵¹^ORCID,Hagino Yoko⁵²,Kotajima-Murakami Hiroko⁵²,Moriya Yuki⁵²,Ikeda Kazutaka⁵²^ORCID,Kim Hyopil⁵³^ORCID,Kaang Bong-Kiun⁵³⁵⁴^ORCID,Otabi Hikari⁵⁵⁵⁶^ORCID,Yoshida Yuta⁵⁵,Toyoda Atsushi⁵⁵⁵⁶⁵⁷^ORCID,Komiyama Noboru H.⁵⁸⁵⁹^ORCID,Grant Seth G. N.⁵⁸⁵⁹^ORCID,Ida-Eto Michiru⁶⁰^ORCID,Narita Masaaki⁶⁰,Matsumoto Ken-ichi⁶¹,Okuda-Ashitaka Emiko⁶²,Ohmori Iori⁶³^ORCID,Shimada Tadayuki⁶⁴,Yamagata Kanato⁶⁴,Ageta Hiroshi⁶⁵,Tsuchida Kunihiro⁶⁵^ORCID,Inokuchi Kaoru⁶⁶⁶⁷⁶⁸^ORCID,Sassa Takayuki⁶⁹^ORCID,Kihara Akio⁶⁹^ORCID,Fukasawa Motoaki⁷⁰^ORCID,Usuda Nobuteru⁷⁰,Katano Tayo⁷¹^ORCID,Tanaka Teruyuki⁷²^ORCID,Yoshihara Yoshihiro⁷³^ORCID,Igarashi Michihiro⁷⁴⁷⁵,Hayashi Takashi⁷⁶^ORCID,Ishikawa Kaori⁷⁷⁷⁸^ORCID,Yamamoto Satoshi⁷⁹,Nishimura Naoya⁷⁹,Nakada Kazuto⁷⁷⁷⁸,Hirotsune Shinji⁸⁰,Egawa Kiyoshi⁸¹,Higashisaka Kazuma⁸²,Tsutsumi Yasuo⁸²,Nishihara Shoko⁸³,Sugo Noriyuki⁸⁴,Yagi Takeshi⁸⁴,Ueno Naoto⁸⁵^ORCID,Yamamoto Tomomi⁸⁶,Kubo Yoshihiro⁸⁶^ORCID,Ohashi Rie⁸⁷⁸⁸⁸⁹,Shiina Nobuyuki⁸⁷⁸⁸⁸⁹^ORCID,Shimizu Kimiko⁹⁰^ORCID,Higo-Yamamoto Sayaka⁹¹,Oishi Katsutaka⁹¹⁹²⁹³⁹⁴^ORCID,Mori Hisashi⁹⁵^ORCID,Furuse Tamio⁹⁶^ORCID,Tamura Masaru⁹⁶,Shirakawa Hisashi⁴⁷^ORCID,Sato Daiki X.¹⁹⁷^ORCID,Inoue Yukiko U.⁴^ORCID,Inoue Takayoshi⁴^ORCID,Komine Yuriko⁹⁸^ORCID,Yamamori Tetsuo⁹⁹¹⁰⁰,Sakimura Kenji¹⁰¹¹⁰²^ORCID,Miyakawa Tsuyoshi¹^ORCID

Affiliation:

1. Division of Systems Medical Science, Center for Medical Science, Fujita Health University, Toyoake, Aichi 470-1192, Japan

2. Department of Neurology, National Cerebral and Cardiovascular Center, Suita, Osaka 564- 8565, Japan

3. Laboratory of Genome Science, Biosignal Genome Resource Center, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Gunma 371-8512, Japan

4. Department of Biochemistry and Cellular Biology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187-8502, Japan

5. Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Kyoto, Kyoto 615-8510, Japan

6. Department of Cellular Neurobiology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan

7. Department of Molecular and Cellular Physiology, Graduate School of Medicine, University of the Ryukyus, Nishihara, Okinawa 903-0215, Japan

8. Department of Neurology, Jena University Hospital, 07747 Jena, Germany

9. Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Fukuoka 812-8582, Japan

10. Laboratory of Mammalian Neural Circuits, National Institute of Genetics, Mishima, Shizuoka 411-8540, Japan

11. Department of Molecular Pharmacology and Neurobiology, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, Japan

12. Laboratory for Neurogenetics, RIKEN Center for Brain Science, Wako, Saitama 351-0198, Japan

13. Department of Neurodevelopmental Disorder Genetics, Institute of Brain Sciences, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467-8601, Japan

14. Laboratory of Structural Physiology, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo 113-0033, Japan

15. Department of Physiology, Kitasato University School of Medicine, Sagamihara, Kanagawa 252-0374, Japan

16. International Research Center for Neurointelligence (WPI-IRCN), UTIAS, The University of Tokyo, Tokyo 113-0033, Japan

17. Research Core Center, Tokyo Medical and Dental University, Tokyo 113-8510, Japan

18. Department of Stem Cell Regulation, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 113-8510, Japan

19. Department of Biochemistry, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt

20. Department of Behavioral Physiology, Graduate School of Innovative Life Science, University of Toyama, Toyama, Toyama 930-0194, Japan

21. Medical Research Institute, Kanazawa Medical University, Uchinada, Kahoku, Ishikawa920-0293, Japan

22. Department of Behavioral Physiology, Faculty of Medicine, University of Toyama, Toyama, Toyama 930-0194, Japan

23. Department of Neuroscience, Southern Research, Birmingham, AL 35205, USA

24. Institute for Developmental Research, Aichi Developmental Disability Center, Kasugai, Aichi 480-0392, Japan

25. Department of Endocrinology, Diabetes and Metabolism, School of Medicine, Fujita Health University, Toyoake, Aichi 470-1192, Japan

26. Department of Neuropsychiatry, Hyogo Medical University, School of Medicine, Nishinomiya, Hyogo 663-8501, Japan

27. Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA

28. Department of Molecular Neurobiology, Faculty of Medicine, Kagawa University, Kita-gun, Kagawa 761-0793, Japan

29. Department of Peripheral Nervous System Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187-8502, Japan

30. Department of Molecular & Cellular Physiology, Shinshu University School of Medicine, Matsumoto, Nagano 390-8621, Japan

31. Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187-8502, Japan

32. Department of Psychiatry, Teikyo University School of Medicine, Tokyo 173-8605, Japan

33. Program of Developmental Neurobiology, National Institute of Child Health and Human Development, National Institute of Health, Bethesda, MD 20892, USA

34. Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka 565-0871, Japan

35. Department of Pharmacology, Graduate School of Dentistry, Osaka University, Suita, Osaka 565-0871, Japan

36. United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University and University of Fukui, Suita, Osaka 565-0871, Japan

37. Division of Bioscience, Institute for Datability Science, Osaka University, Suita, Osaka 565-0871, Japan

38. Transdimensional Life Imaging Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Suita, Osaka 565-0871, Japan

39. Department of Molecular Pharmaceutical Science, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan

40. RIKEN Brain Science Institute, Wako, Saitama 351-0198, Japan

41. Department of Physiology and Cell Biology, Kobe University School of Medicine, Kobe, Hyogo 650-0017, Japan

42. Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Center for Brain Science, Wako, Saitama 351-0198, Japan

43. Institute of Biology and Environmental Sciences, Carl von Ossietzky University of Oldenburg, Oldenburg 26129, Germany

44. Department of Psychiatry and Behavioral Science, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan

45. Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA

46. Department of Pharmacology, Kyoto Prefectural University of Medicine, Kyoto, Kyoto 602-8566, Japan

47. Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Kyoto 606-8501, Japan

48. Department of Biomedical Science, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Aichi 467-8603, Japan

49. Laboratory of Medical Neuroscience, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Gunma 371-8512, Japan

50. Laboratory for Multi-scale Biological Psychiatry, RIKEN Center for Brain Science, Wako, Saitama 351-0198, Japan

51. Institut des Neurosciences Cellulaires et Intégratives, Centre National de la Recherche Scientifique, Université de Strasbourg, Strasbourg 67000, France

52. Addictive Substance Project, Tokyo Metropolitan Institute of Medical Science, Tokyo 156- 8506, Japan

53. Department of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul 08826, South Korea

54. Center for Cognition and Sociality, Institute for Basic Science (IBS), Daejeon 34141, South Korea

55. College of Agriculture, Ibaraki University, Ami, Ibaraki 300-0393, Japan

56. United Graduate School of Agricultural Science, Tokyo University of Agriculture and Technology, Fuchu, Tokyo 183-8538, Japan

57. Ibaraki University Cooperation between Agriculture and Medical Science (IUCAM), Ami, Ibaraki 300-0393, Japan

58. Genes to Cognition Program, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh EH16 4SB, UK

59. Simons Initiative for the Developing Brain, Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh EH8 9XF, UK

60. Department of Developmental and Regenerative Medicine, Mie University, Graduate School of Medicine, Tsu, Mie 514-8507, Japan

61. Department of Biosignaling and Radioisotope Experiment, Interdisciplinary Center for Science Research, Organization for Research and Academic Information, Shimane University, Izumo, Shimane 693-8501, Japan

62. Department of Biomedical Engineering, Osaka Institute of Technology, Osaka 535-8585, Japan

63. Department of Physiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Okayama 700-8530, Japan

64. Child brain project, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan

65. Division for Therapies Against Intractable Diseases, Center for Medical Science, Fujita Health University, Toyoake, Aichi 470-1192, Japan

66. Research Center for Idling Brain Science, University of Toyama, Toyama, Toyama 930- 0194, Japan

67. Department of Biochemistry, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Toyama 930-0194, Japan

68. Core Research for Evolutionary Science and Technology (CREST), Japan Science and Technology Agency (JST), University of Toyama, Toyama, Toyama 930-0194, Japan

69. Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Hokkaido 060-0812, Japan

70. Department of Anatomy II, Fujita Health University School of Medicine, Toyoake, Aichi 470-1192, Japan

71. Department of Medical Chemistry, Kansai Medical University, Hirakata, Osaka 573-1010, Japan

72. Department of Developmental Medical Sciences, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan

73. Laboratory for Systems Molecular Ethology, RIKEN Center for Brain Science, Wako, Saitama 351-0198, Japan

74. Department of Neurochemistry and Molecular Cell Biology, School of Medicine, and Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Niigata 951- 8510, Japan

75. Transdiciplinary Research Program, Niigata University, Niigata, Niigata 951-8510, Japan

76. Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki 305-8566, Japan

77. Faculty of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki 305- 8572, Japan

78. Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8572, Japan

79. Integrated Technology Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd, Fujisawa, Kanagawa 251-8555, Japan

80. Department of Genetic Disease Research, Osaka City University Graduate School of Medicine, Osaka, Osaka 545-8585, Japan

81. Department of Pediatrics, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido 060-8638, Japan

82. Laboratory of Toxicology and Safety Science, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka 565-0871, Japan

83. Glycan & Life Systems Integration Center (GaLSIC), Soka University, Tokyo 192-8577, Japan

84. Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka 565-0871, Japan

85. National Institute for Basic Biology, Laboratory of Morphogenesis, Okazaki, Aichi 444- 8585, Japan

86. Division of Biophysics and Neurobiology, National Institute for Physiological Sciences, Okazaki, Aichi 444-8585, Japan

87. Laboratory of Neuronal Cell Biology, National Institute for Basic Biology, Okazaki, Aichi 444-8585, Japan

88. Department of Basic Biology, SOKENDAI (Graduate University for Advanced Studies), Okazaki, Aichi 444-8585, Japan

89. Exploratory Research Center on Life and Living Systems (ExCELLS), National Institutes of Natural Sciences, Okazaki, Aichi 444-8585, Japan

90. Department of Biological Sciences, School of Science, The University of Tokyo, Tokyo 113-0033, Japan

91. Healthy Food Science Research Group, Cellular and Molecular Biotechnology Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki 305-8566, Japan

92. Department of Applied Biological Science, Graduate School of Science and Technology, Tokyo University of Science, Noda, Chiba 278-8510, Japan

93. Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Chiba 277-8562, Japan

94. School of Integrative and Global Majors (SIGMA), University of Tsukuba, Tsukuba, Ibaraki 305-8577, Japan

95. Department of Molecular Neuroscience, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Toyama 930-0194, Japan

96. Technology and Development Team for Mouse Phenotype Analysis, Japan Mouse Clinic, RIKEN BioResource Research Center (BRC), Tsukuba, Ibaraki 305-0074, Japan

97. Graduate School of Life Sciences, Tohoku University, Sendai, Miyagi 980-8578, Japan

98. Young Researcher Support Group, Research Enhancement Strategy Office, National Institute for Basic Biology, National Institute of Natural Sciences, Okazaki, Aichi 444-8585, Japan

99. Division of Brain Biology, National Institute for Basic Biology, Okazaki, Aichi 444-8585, Japan

100. Laboratory for Molecular Analysis of Higher Brain Function, RIKEN Center for Brain Science, Wako, Saitama 351-0198, Japan

101. Department of Cellular Neurobiology, Brain Research Institute, Niigata University, Niigata, Niigata 951-8585, Japan

102. Department of Animal Model Development, Brain Research Institute, Niigata University, Niigata, Niigata 951-8585, Japan

Abstract

Increased levels of lactate, an end-product of glycolysis, have been proposed as a potential surrogate marker for metabolic changes during neuronal excitation. These changes in lactate levels can result in decreased brain pH, which has been implicated in patients with various neuropsychiatric disorders. We previously demonstrated that such alterations are commonly observed in five mouse models of schizophrenia, bipolar disorder, and autism, suggesting a shared endophenotype among these disorders rather than mere artifacts due to medications or agonal state. However, there is still limited research on this phenomenon in animal models, leaving its generality across other disease animal models uncertain. Moreover, the association between changes in brain lactate levels and specific behavioral abnormalities remains unclear. To address these gaps, the International Brain pH Project Consortium investigated brain pH and lactate levels in 109 strains/conditions of 2,294 animals with genetic and other experimental manipulations relevant to neuropsychiatric disorders. Systematic analysis revealed that decreased brain pH and increased lactate levels were common features observed in multiple models of depression, epilepsy, Alzheimer’s disease, and some additional schizophrenia models. While certain autism models also exhibited decreased pH and increased lactate levels, others showed the opposite pattern, potentially reflecting subpopulations within the autism spectrum. Furthermore, utilizing large-scale behavioral test battery, a multivariate cross-validated prediction analysis demonstrated that poor working memory performance was predominantly associated with increased brain lactate levels. Importantly, this association was confirmed in an independent cohort of animal models. Collectively, these findings suggest that altered brain pH and lactate levels, which could be attributed to dysregulated excitation/inhibition balance, may serve as transdiagnostic endophenotypes of debilitating neuropsychiatric disorders characterized by cognitive impairment, irrespective of their beneficial or detrimental nature.

Publisher

eLife Sciences Publications, Ltd

Link

https://elifesciences.org/reviewed-preprints/89376v2/pdf

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