From autism to Alzheimer’s: A large-scale animal study links brain pH changes to wide-ranging cognitive issues

A global collaborative research group comprising 131 researchers from 105 laboratories across seven countries announces a groundbreaking research paper submitted to eLife. Titled "Large-scale Animal Model Study Uncovers Altered Brain pH and Lactate Levels as a Transdiagnostic Endophenotype of Neuropsychiatric Disorders Involving Cognitive Impairment," the study identifies brain energy metabolism dysfunction leading to altered pH and lactate levels as common hallmarks in numerous animal models of neuropsychiatric and neurodegenerative disorders, such as intellectual disability, autism spectrum disorders, schizophrenia, bipolar disorder, depressive disorders, and Alzheimer’s disease.

At the forefront of neuroscience research, the research group sheds light on altered energy metabolism as a key factor in various neuropsychiatric and neurodegenerative disorders. While considered controversial, an elevated lactate level and the resulting decrease in pH is now also proposed as a potential primary component of these diseases. Unlike previous assumptions associating these changes with external factors like medication^a, the research group's previous findings suggest that they may be intrinsic to the disorders. This conclusion was drawn from five animal models of schizophrenia/developmental disorders, bipolar disorder, and autism, which are exempt from such confounding factors^b. However, research on brain pH and lactate levels in animal models of other neuropsychiatric and neurological disorders has been limited. Until now, it was unclear whether such changes in the brain were a common phenomenon. Additionally, the relationship between alterations in brain pH and lactate levels and specific behavioral abnormalities had not been clearly established.

This study, encompassing 109 strains/conditions of mice, rats, and chicks, including animal models related to neuropsychiatric conditions, reveals that changes in brain pH and lactate levels are a common feature in a diverse range of animal models of diseases, including schizophrenia/developmental disorders, bipolar disorder, autism, as well as models of depression, epilepsy, and Alzheimer's disease. This study's significant insights include:

I. Common Phenomenon Across Disorders: About 30% of the 109 types of animal models exhibited significant changes in brain pH and lactate levels, emphasizing the widespread occurrence of energy metabolism changes in the brain across various neuropsychiatric conditions.

II. Environmental Factors as a Cause: Models simulating depression through psychological stress, and those induced to develop diabetes or colitis, which have a high comorbidity risk for depression, showed decreased brain pH and increased lactate levels. Various acquired environmental factors could contribute to these changes.

III. Cognitive Impairment Link: A comprehensive analysis integrating behavioral test data revealed a predominant association between increased brain lactate levels and impaired working memory, illuminating an aspect of cognitive dysfunction.

IV. Confirmation in Independent Cohort: These associations, particularly between higher brain lactate levels and poor working memory performance, were validated in an independent cohort of animal models, reinforcing the initial findings.

V. Autism Spectrum Complexity: Variable responses were noted in autism models, with some showing increased pH and decreased lactate levels, suggesting subpopulations within the autism spectrum with diverse metabolic patterns.

"This is the first and largest systematic study evaluating brain pH and lactate levels across a range of animal models for neuropsychiatric and neurodegenerative disorders. Our findings may lay the groundwork for new approaches to develop the transdiagnostic characterization of different disorders involving cognitive impairment," states Dr. Hideo Hagihara, the study's lead author.

Professor Tsuyoshi Miyakawa, the corresponding author, explains, "This research could be a stepping stone towards identifying shared therapeutic targets in various neuropsychiatric disorders. Future studies will center on uncovering treatment strategies that are effective across diverse animal models with brain pH changes. This could significantly contribute to developing tailored treatments for patient subgroups characterized by specific alterations in brain energy metabolism."

In this paper, the mechanistic insights into the reduction in pH and the increase in lactate levels remain elusive. However, it is known that lactate production increases in response to neural hyperactivity to meet the energy demand, and the authors seem to think this might be the underlying reason.

References

a. Halim ND, Lipska BK, Hyde TM, Deep-Soboslay A, Saylor EM, Herman M, et al (2008). Increased lactate levels and reduced pH in postmortem brains of schizophrenics: medication confounds. Journal of Neuroscience Methods 169(1): 208–213.

b. Hagihara H, Catts VS, Katayama Y, Shoji H, Takagi T, Huang FL, et al (2018). Decreased Brain pH as a Shared Endophenotype of Psychiatric Disorders. Neuropsychopharmacology 43(3): 459–468.

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

Journal
eLife

Authors

Hideo Hagihara¹, Hirotaka Shoji¹, Satoko Hattori¹, Giovanni Sala¹, Yoshihiro Takamiya¹, Mika Tanaka¹, Masafumi Ihara², Mihiro Shibutani³, Izuho Hatada³, Kei Hori⁴, Mikio Hoshino⁴, Akito Nakao⁵, Yasuo Mori⁵, Shigeo Okabe⁶, Masayuki Matsushita⁷, Anja Urbach⁸, Yuta Katayama⁹, Akinobu Matsumoto⁹, Keiichi I. Nakayama⁹, Shota Katori¹⁰, Takuya Sato¹⁰, Takuji Iwasato¹⁰, Haruko Nakamura¹¹, Yoshio Goshima¹¹, Matthieu Raveau¹², Tetsuya Tatsukawa¹², Kazuhiro Yamakawa^{12, 13}, Noriko Takahashi^{14, 15}, Haruo Kasai^{14, 16}, Johji Inazawa¹⁷, Ikuo Nobuhisa¹⁸, Tetsushi Kagawa¹⁸, Tetsuya Taga¹⁸, Mohamed Darwish^{19, 20}, Hirofumi Nishizono²¹, Keizo Takao^{20, 22}, Kiran Sapkota²³, Kazutoshi Nakazawa²³, Tsuyoshi Takagi²⁴, Haruki Fujisawa²⁵, Yoshihisa Sugimura²⁵, Kyosuke Yamanishi²⁶, Lakshmi Rajagopal²⁷, Nanette Deneen Hannah²⁷, Herbert Y. Meltzer²⁷, Tohru Yamamoto²⁸, Shuji Wakatsuki²⁹, Toshiyuki Araki²⁹, Katsuhiko Tabuchi³⁰, Tadahiro Numakawa³¹, Hiroshi Kunugi^{31, 32}, Freesia L. Huang³³, Atsuko Hayata-Takano^34-36, Hitoshi Hashimoto^{34, 36-39}, Kota Tamada^{40, 41}, Toru Takumi^{40, 41}, Takaoki Kasahara^{42, 43}, Tadafumi Kato^{42, 44}, Isabella A. Graef⁴⁵, Gerald R. Crabtree⁴⁵, Nozomi Asaoka⁴⁶, Hikari Hatakama⁴⁷, Shuji Kaneko⁴⁷, Takao Kohno⁴⁸, Mitsuharu Hattori⁴⁸, Yoshio Hoshiba⁴⁹, Ryuhei Miyake⁵⁰, Kisho Obi-Nagata⁵⁰, Akiko Hayashi-Takagi^{49, 50}, Léa J. Becker⁵¹, Ipek Yalcin⁵¹, Yoko Hagino⁵², Hiroko Kotajima-Murakami⁵², Yuki Moriya⁵², Kazutaka Ikeda⁵², Hyopil Kim^{53, 54}, Bong-Kiun Kaang^{53, 55}, Hikari Otabi^{56, 57}, Yuta Yoshida⁵⁶, Atsushi Toyoda^56-58, Noboru H. Komiyama^{59, 60}, Seth G. N. Grant^{59, 60}, Michiru Ida-Eto⁶¹, Masaaki Narita⁶¹, Ken-ichi Matsumoto⁶², Emiko Okuda-Ashitaka⁶³, Iori Ohmori⁶⁴, Tadayuki Shimada⁶⁵, Kanato Yamagata⁶⁵, Hiroshi Ageta⁶⁶, Kunihiro Tsuchida⁶⁶, Kaoru Inokuchi^67-69, Takayuki Sassa⁷⁰, Akio Kihara⁷⁰, Motoaki Fukasawa⁷¹, Nobuteru Usuda⁷¹, Tayo Katano⁷², Teruyuki Tanaka⁷³, Yoshihiro Yoshihara⁷⁴, Michihiro Igarashi^{75, 76}, Takashi Hayashi⁷⁷, Kaori Ishikawa^{78, 79}, Satoshi Yamamoto⁸⁰, Naoya Nishimura⁸⁰, Kazuto Nakada^{78, 79}, Shinji Hirotsune⁸¹, Kiyoshi Egawa⁸², Kazuma Higashisaka⁸³, Yasuo Tsutsumi⁸³, Shoko Nishihara⁸⁴, Noriyuki Sugo⁸⁵, Takeshi Yagi⁸⁵, Naoto Ueno⁸⁶, Tomomi Yamamoto⁸⁷, Yoshihiro Kubo⁸⁷, Rie Ohashi^88-90, Nobuyuki Shiina^88-90, Kimiko Shimizu⁹¹, Sayaka Higo-Yamamoto⁹², Katsutaka Oishi^92-95, Hisashi Mori⁹⁶, Tamio Furuse⁹⁷, Masaru Tamura⁹⁷, Hisashi Shirakawa⁹⁸, Daiki X. Sato^{1, 99}, Yukiko U. Inoue¹⁰⁰, Takayoshi Inoue¹⁰⁰, Yuriko Komine^{101, 102} , Tetsuo Yamamori^{102, 103}, Kenji Sakimura^{104, 105}, Tsuyoshi Miyakawa¹

Affiliations

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, 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, Republic of Korea
54. Department of Biomedical Engineering, Johns Hopkins School of Medicine, Baltimore, MD21205, USA
55. Center for Cognition and Sociality, Institute for Basic Science (IBS), Daejeon 34141, Republic of Korea
56. College of Agriculture, Ibaraki University, Ami, Ibaraki 300-0393, Japan
57. United Graduate School of Agricultural Science, Tokyo University of Agriculture and Technology, Fuchu, Tokyo 183-8538, Japan
58. Ibaraki University Cooperation between Agriculture and Medical Science (IUCAM), Ami, Ibaraki 300-0393, Japan
59. Genes to Cognition Program, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh EH16 4SB, UK
60. Simons Initiative for the Developing Brain, Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh EH8 9XF, UK
61. Department of Developmental and Regenerative Medicine, Mie University, Graduate School of Medicine, Tsu, Mie 514-8507, Japan
62. Department of Biosignaling and Radioisotope Experiment, Interdisciplinary Center for Science Research, Organization for Research and Academic Information, Shimane University, Izumo, Shimane 693-8501, Japan
63. Department of Biomedical Engineering, Osaka Institute of Technology, Osaka 535-8585, Japan
64. Department of Physiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Okayama 700-8530, Japan
65. Child brain project, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan
66. Division for Therapies Against Intractable Diseases, Center for Medical Science, Fujita Health University, Toyoake, Aichi 470-1192, Japan
67. Research Center for Idling Brain Science, University of Toyama, Toyama, Toyama 930-0194, Japan
68. Department of Biochemistry, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Toyama 930-0194, Japan
69. Core Research for Evolutionary Science and Technology (CREST), Japan Science and Technology Agency (JST), University of Toyama, Toyama, Toyama 930-0194, Japan
70. Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Hokkaido 060-0812, Japan
71. Department of Anatomy II, Fujita Health University School of Medicine, Toyoake, Aichi 470-1192, Japan
72. Department of Medical Chemistry, Kansai Medical University, Hirakata, Osaka 573-1010, Japan
73. Department of Developmental Medical Sciences, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan
74. Laboratory for Systems Molecular Ethology, RIKEN Center for Brain Science, Wako, Saitama 351-0198, Japan
75. 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
76. Transdiciplinary Research Program, Niigata University, Niigata, Niigata 951-8510, Japan
77. Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki 305-8566, Japan
78. Faculty of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8572, Japan
79. Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8572, Japan
80. Integrated Technology Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd, Fujisawa, Kanagawa 251-8555, Japan
81. Department of Genetic Disease Research, Osaka City University Graduate School of Medicine, Osaka, Osaka 545-8585, Japan
82. Department of Pediatrics, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido 060-8638, Japan
83. Laboratory of Toxicology and Safety Science, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka 565-0871, Japan
84. Glycan & Life Systems Integration Center (GaLSIC), Soka University, Tokyo 192-8577, Japan
85. Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka 565-0871, Japan
86. National Institute for Basic Biology, Laboratory of Morphogenesis, Okazaki, Aichi 444-8585, Japan
87. Division of Biophysics and Neurobiology, National Institute for Physiological Sciences, Okazaki, Aichi 444-8585, Japan
88. Laboratory of Neuronal Cell Biology, National Institute for Basic Biology, Okazaki, Aichi 444-8585, Japan
89. Department of Basic Biology, SOKENDAI (Graduate University for Advanced Studies), Okazaki, Aichi 444-8585, Japan
90. Exploratory Research Center on Life and Living Systems (ExCELLS), National Institutes of Natural Sciences, Okazaki, Aichi 444-8585, Japan
91. Department of Biological Sciences, School of Science, The University of Tokyo, Tokyo 113-0033, Japan
92. 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
93. Department of Applied Biological Science, Graduate School of Science and Technology, Tokyo University of Science, Noda, Chiba 278-8510, Japan
94. Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Chiba 277-8562, Japan
95. School of Integrative and Global Majors (SIGMA), University of Tsukuba, Tsukuba, Ibaraki 305-8577, Japan
96. Department of Molecular Neuroscience, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Toyama 930-0194, Japan
97. Mouse Phenotype Analysis Division, Japan Mouse Clinic, RIKEN BioResource Research Center (BRC), Tsukuba, Ibaraki 305-0074, Japan
98. Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Kyoto 606-8501, Japan
99. Graduate School of Life Sciences, Tohoku University, Sendai, Miyagi 980-8578, Japan
100. Department of Biochemistry and Cellular Biology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187-8502, Japan
101. Young Researcher Support Group, Research Enhancement Strategy Office, National Institute for Basic Biology, National Institute of Natural Sciences, Okazaki, Aichi 444-8585, Japan
102. Division of Brain Biology, National Institute for Basic Biology, Okazaki, Aichi 444-8585, Japan
103. Laboratory for Molecular Analysis of Higher Brain Function, RIKEN Center for Brain Science, Wako, Saitama 351-0198, Japan
104. Department of Cellular Neurobiology, Brain Research Institute, Niigata University, Niigata, Niigata 951-8585, Japan
105. Department of Animal Model Development, Brain Research Institute, Niigata University, Niigata, Niigata 951-8585, Japan