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^ORCID,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

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 and 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, Nagoya

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 Center, 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 Institute 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, Wako, Saitama

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

55. College of Agriculture, Ibaraki University

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

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

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

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

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

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

62. Department of Biomedical Engineering, Osaka Institute of Technology

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

64. Child brain project, Tokyo Metropolitan Institute of Medical Science

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

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

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

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

69. Faculty of Pharmaceutical Sciences, Hokkaido University

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

71. Department of Medical Chemistry, Kansai Medical University

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

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

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

75. Transdiciplinary Research Program, Niigata University

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

77. Faculty of Life and Environmental Sciences, University of Tsukuba

78. Graduate School of Life and Environmental Sciences, University of Tsukuba

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

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

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

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

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

84. Graduate School of Frontier Biosciences, Osaka University

85. National Institute for Basic Biology, Laboratory of Morphogenesis

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

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

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

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

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

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

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

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

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

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

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

97. Graduate School of Life Sciences, Tohoku University

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

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

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

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

102. 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 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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