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:2024-03-26 Issue: Volume:12 Page:
ISSN:2050-084X
Container-title:eLife
language:en
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Author:

Hagihara Hideo¹^ORCID,Shoji Hirotaka¹,Hattori Satoko¹,Sala Giovanni¹,Takamiya Yoshihiro¹,Tanaka Mika¹,Ihara Masafumi²,Shibutani Mihiro³,Hatada Izuho³,Hori Kei⁴,Hoshino Mikio⁴^ORCID,Nakao Akito⁵^ORCID,Mori Yasuo⁵,Okabe Shigeo⁶^ORCID,Matsushita Masayuki⁷,Urbach Anja⁸,Katayama Yuta⁹,Matsumoto Akinobu⁹,Nakayama Keiichi I⁹,Katori Shota¹⁰,Sato Takuya¹⁰,Iwasato Takuji¹⁰,Nakamura Haruko¹¹,Goshima Yoshio¹¹,Raveau Matthieu¹²,Tatsukawa Tetsuya¹²,Yamakawa Kazuhiro¹²¹³^ORCID,Takahashi Noriko¹⁴¹⁵,Kasai Haruo¹⁴¹⁶^ORCID,Inazawa Johji¹⁷,Nobuhisa Ikuo¹⁸,Kagawa Tetsushi¹⁸,Taga Tetsuya¹⁸,Darwish Mohamed¹⁹²⁰,Nishizono Hirofumi²¹,Takao Keizo²⁰²²^ORCID,Sapkota Kiran²³,Nakazawa Kazutoshi²³,Takagi Tsuyoshi²⁴,Fujisawa Haruki²⁵,Sugimura Yoshihisa²⁵,Yamanishi Kyosuke²⁶^ORCID,Rajagopal Lakshmi²⁷,Hannah Nanette Deneen²⁷,Meltzer Herbert Y²⁷,Yamamoto Tohru²⁸^ORCID,Wakatsuki Shuji²⁹,Araki Toshiyuki²⁹,Tabuchi Katsuhiko³⁰,Numakawa Tadahiro³¹,Kunugi Hiroshi³¹³²,Huang Freesia L³³,Hayata-Takano Atsuko³⁴³⁵³⁶,Hashimoto Hitoshi³⁴³⁶³⁷³⁸³⁹^ORCID,Tamada Kota⁴⁰⁴¹^ORCID,Takumi Toru⁴⁰⁴¹^ORCID,Kasahara Takaoki⁴²⁴³^ORCID,Kato Tadafumi⁴²⁴⁴,Graef Isabella A⁴⁵,Crabtree Gerald R⁴⁵,Asaoka Nozomi⁴⁶,Hatakama Hikari⁴⁷,Kaneko Shuji⁴⁷,Kohno Takao⁴⁸^ORCID,Hattori Mitsuharu⁴⁸,Hoshiba Yoshio⁴⁹,Miyake Ryuhei⁵⁰,Obi-Nagata Kisho⁵⁰,Hayashi-Takagi Akiko⁴⁹⁵⁰,Becker Léa J⁵¹,Yalcin Ipek⁵¹,Hagino Yoko⁵²,Kotajima-Murakami Hiroko⁵²,Moriya Yuki⁵²,Ikeda Kazutaka⁵²,Kim Hyopil⁵³⁵⁴,Kaang Bong-Kiun⁵³⁵⁵^ORCID,Otabi Hikari⁵⁶⁵⁷,Yoshida Yuta⁵⁶,Toyoda Atsushi⁵⁶⁵⁷⁵⁸,Komiyama Noboru H⁵⁹⁶⁰,Grant Seth GN⁵⁹⁶⁰^ORCID,Ida-Eto Michiru⁶¹,Narita Masaaki⁶¹,Matsumoto Ken-ichi⁶²,Okuda-Ashitaka Emiko⁶³,Ohmori Iori⁶⁴,Shimada Tadayuki⁶⁵^ORCID,Yamagata Kanato⁶⁵,Ageta Hiroshi⁶⁶,Tsuchida Kunihiro⁶⁶^ORCID,Inokuchi Kaoru⁶⁷⁶⁸⁶⁹^ORCID,Sassa Takayuki⁷⁰^ORCID,Kihara Akio⁷⁰^ORCID,Fukasawa Motoaki⁷¹,Usuda Nobuteru⁷¹,Katano Tayo⁷²,Tanaka Teruyuki⁷³,Yoshihara Yoshihiro⁷⁴,Igarashi Michihiro⁷⁵⁷⁶^ORCID,Hayashi Takashi⁷⁷^ORCID,Ishikawa Kaori⁷⁸⁷⁹^ORCID,Yamamoto Satoshi⁸⁰,Nishimura Naoya⁸⁰,Nakada Kazuto⁷⁸⁷⁹,Hirotsune Shinji⁸¹,Egawa Kiyoshi⁸²,Higashisaka Kazuma⁸³,Tsutsumi Yasuo⁸³,Nishihara Shoko⁸⁴^ORCID,Sugo Noriyuki⁸⁵,Yagi Takeshi⁸⁵,Ueno Naoto⁸⁶^ORCID,Yamamoto Tomomi⁸⁷,Kubo Yoshihiro⁸⁷^ORCID,Ohashi Rie⁸⁸⁸⁹⁹⁰,Shiina Nobuyuki⁸⁸⁸⁹⁹⁰^ORCID,Shimizu Kimiko⁹¹^ORCID,Higo-Yamamoto Sayaka⁹²,Oishi Katsutaka⁹²⁹³⁹⁴⁹⁵^ORCID,Mori Hisashi⁹⁶^ORCID,Furuse Tamio⁹⁷,Tamura Masaru⁹⁷,Shirakawa Hisashi⁴⁷^ORCID,Sato Daiki X¹⁹⁸^ORCID,Inoue Yukiko U⁴^ORCID,Inoue Takayoshi⁴,Komine Yuriko⁹⁹¹⁰⁰^ORCID,Yamamori Tetsuo¹⁰⁰¹⁰¹,Sakimura Kenji¹⁰²¹⁰³^ORCID,Miyakawa Tsuyoshi¹^ORCID

Affiliation:

1. Division of Systems Medical Science, Center for Medical Science, Fujita Health University

2. Department of Neurology, National Cerebral and Cardiovascular Center

3. Laboratory of Genome Science, Biosignal Genome Resource Center, Institute for Molecular and Cellular Regulation, Gunma University

4. Department of Biochemistry and Cellular Biology, National Institute of Neuroscience, National Center of Neurology and Psychiatry

5. Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University

6. Department of Cellular Neurobiology, Graduate School of Medicine, The University of Tokyo

7. Department of Molecular Cellular Physiology, Graduate School of Medicine, University of the Ryukyus

8. Department of Neurology, Jena University Hospital

9. Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University

10. Laboratory of Mammalian Neural Circuits, National Institute of Genetics

11. Department of Molecular Pharmacology and Neurobiology, Yokohama City University Graduate School of Medicine

12. Laboratory for Neurogenetics, RIKEN Center for Brain Science

13. Department of Neurodevelopmental Disorder Genetics, Institute of Brain Sciences, Nagoya City University Graduate School of Medical Sciences

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

15. Department of Physiology, Kitasato University School of Medicine

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

17. Research Core, Tokyo Medical and Dental University

18. Department of Stem Cell Regulation, Medical Research Institute, Tokyo Medical and Dental University

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

20. Department of Behavioral Physiology, Graduate School of Innovative Life Science, University of Toyama

21. Medical Research Institute, Kanazawa Medical University

22. Department of Behavioral Physiology, Faculty of Medicine, University of Toyama

23. Department of Neuroscience, Southern Research

24. Institute for Developmental Research, Aichi Developmental Disability Center

25. Department of Endocrinology, Diabetes and Metabolism, School of Medicine, Fujita Health University

26. Department of Neuropsychiatry, Hyogo Medical University School of Medicine

27. Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine

28. Department of Molecular Neurobiology, Faculty of Medicine, Kagawa University

29. Department of Peripheral Nervous System Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry

30. Department of Molecular & Cellular Physiology, Shinshu University School of Medicine

31. Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry

32. Department of Psychiatry, Teikyo University School of Medicine

33. Program of Developmental Neurobiology, National Institute of Child Health and Human Development, National Institutes of Health

34. Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University

35. Department of Pharmacology, Graduate School of Dentistry, Osaka University

36. United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University and University of Fukui

37. Division of Bioscience, Institute for Datability Science, Osaka University

38. Transdimensional Life Imaging Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University

39. Department of Molecular Pharmaceutical Science, Graduate School of Medicine, Osaka University

40. RIKEN Brain Science Institute

41. Department of Physiology and Cell Biology, Kobe University School of Medicine

42. Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Center for Brain Science

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

44. Department of Psychiatry and Behavioral Science, Juntendo University Graduate School of Medicine

45. Department of Pathology, Stanford University School of Medicine

46. Department of Pharmacology, Kyoto Prefectural University of Medicine

47. Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University

48. Department of Biomedical Science, Graduate School of Pharmaceutical Sciences, Nagoya City University

49. Laboratory of Medical Neuroscience, Institute for Molecular and Cellular Regulation, Gunma University

50. Laboratory for Multi-scale Biological Psychiatry, RIKEN Center for Brain Science

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

52. Addictive Substance Project, Tokyo Metropolitan Institute of Medical Science

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

54. Department of Biomedical Engineering, Johns Hopkins School of Medicine

55. Center for Cognition and Sociality, Institute for Basic Science (IBS)

56. College of Agriculture, Ibaraki University

57. United Graduate School of Agricultural Science, Tokyo University of Agriculture and Technology

58. Ibaraki University Cooperation between Agriculture and Medical Science (IUCAM)

59. Genes to Cognition Program, Centre for Clinical Brain Sciences, University of Edinburgh

60. Simons Initiative for the Developing Brain, Centre for Discovery Brain Sciences, University of Edinburgh

61. Department of Developmental and Regenerative Medicine, Mie University, Graduate School of Medicine

62. Department of Biosignaling and Radioisotope Experiment, Interdisciplinary Center for Science Research, Organization for Research and Academic Information, Shimane University

63. Department of Biomedical Engineering, Osaka Institute of Technology

64. Department of Physiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences

65. Child Brain Project, Tokyo Metropolitan Institute of Medical Science

66. Division for Therapies Against Intractable Diseases, Center for Medical Science, Fujita Health University

67. Research Center for Idling Brain Science, University of Toyama

68. Department of Biochemistry, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama

69. Core Research for Evolutionary Science and Technology (CREST), Japan Science and Technology Agency (JST), University of Toyama

70. Faculty of Pharmaceutical Sciences, Hokkaido University

71. Department of Anatomy II, Fujita Health University School of Medicine

72. Department of Medical Chemistry, Kansai Medical University

73. Department of Developmental Medical Sciences, Graduate School of Medicine, The University of Tokyo

74. Laboratory for Systems Molecular Ethology, RIKEN Center for Brain Science

75. Department of Neurochemistry and Molecular Cell Biology, School of Medicine, and Graduate School of Medical and Dental Sciences, Niigata University

76. Transdiciplinary Research Program, Niigata University

77. Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST)

78. Institute of Life and Environmental Sciences, University of Tsukuba

79. Graduate School of Science and Technology, University of Tsukuba

80. Integrated Technology Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd

81. Department of Genetic Disease Research, Osaka City University Graduate School of Medicine

82. Department of Pediatrics, Hokkaido University Graduate School of Medicine

83. Laboratory of Toxicology and Safety Science, Graduate School of Pharmaceutical Sciences, Osaka University

84. Glycan & Life Systems Integration Center (GaLSIC), Soka University

85. Graduate School of Frontier Biosciences, Osaka University

86. Laboratory of Morphogenesis, National Institute for Basic Biology

87. Division of Biophysics and Neurobiology, National Institute for Physiological Sciences

88. Laboratory of Neuronal Cell Biology, National Institute for Basic Biology

89. Department of Basic Biology, SOKENDAI (Graduate University for Advanced Studies)

90. Exploratory Research Center on Life and Living Systems (ExCELLS), National Institutes of Natural Sciences

91. Department of Biological Sciences, School of Science, The University of Tokyo

92. Healthy Food Science Research Group, Cellular and Molecular Biotechnology Research Institute, National Institute of Advanced Industrial Science and Technology (AIST)

93. Department of Applied Biological Science, Graduate School of Science and Technology, Tokyo University of Science

94. Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo

95. School of Integrative and Global Majors (SIGMA), University of Tsukuba

96. Department of Molecular Neuroscience, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama

97. Mouse Phenotype Analysis Division, Japan Mouse Clinic, RIKEN BioResource Research Center (BRC)

98. Graduate School of Life Sciences, Tohoku University

99. Young Researcher Support Group, Research Enhancement Strategy Office, National Institute for Basic Biology, National Institute of Natural Sciences

100. Division of Brain Biology, National Institute for Basic Biology

101. Laboratory for Molecular Analysis of Higher Brain Function, RIKEN Center for Brain Science

102. Department of Cellular Neurobiology, Brain Research Institute, Niigata University

103. Department of Animal Model Development, Brain Research Institute, Niigata University

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 2294 animals with genetic and other experimental manipulations relevant to neuropsychiatric disorders. Systematic analysis revealed that decreased brain pH and increased lactate levels were common features observed in multiple models of depression, epilepsy, Alzheimer’s disease, and some additional schizophrenia models. While certain autism models also exhibited decreased pH and increased lactate levels, others showed the opposite pattern, potentially reflecting subpopulations within the autism spectrum. Furthermore, utilizing large-scale behavioral test battery, a multivariate cross-validated prediction analysis demonstrated that poor working memory performance was predominantly associated with increased brain lactate levels. Importantly, this association was confirmed in an independent cohort of animal models. Collectively, these findings suggest that altered brain pH and lactate levels, which could be attributed to dysregulated excitation/inhibition balance, may serve as transdiagnostic endophenotypes of debilitating neuropsychiatric disorders characterized by cognitive impairment, irrespective of their beneficial or detrimental nature.

Funder

Ministry of Education, Culture, Sports, Science and Technology

Japan Society for the Promotion of Science

Japan Agency for Medical Research and Development

Publisher

eLife Sciences Publications, Ltd

Link

https://cdn.elifesciences.org/articles/89376/elife-89376-v1.pdf

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