eLife (Mar 2024)
Large-scale animal model study uncovers altered brain pH and lactate levels as a transdiagnostic endophenotype of neuropsychiatric disorders involving cognitive impairment
- Hideo Hagihara,
- Hirotaka Shoji,
- Satoko Hattori,
- Giovanni Sala,
- Yoshihiro Takamiya,
- Mika Tanaka,
- Masafumi Ihara,
- Mihiro Shibutani,
- Izuho Hatada,
- Kei Hori,
- Mikio Hoshino,
- Akito Nakao,
- Yasuo Mori,
- Shigeo Okabe,
- Masayuki Matsushita,
- Anja Urbach,
- Yuta Katayama,
- Akinobu Matsumoto,
- Keiichi I Nakayama,
- Shota Katori,
- Takuya Sato,
- Takuji Iwasato,
- Haruko Nakamura,
- Yoshio Goshima,
- Matthieu Raveau,
- Tetsuya Tatsukawa,
- Kazuhiro Yamakawa,
- Noriko Takahashi,
- Haruo Kasai,
- Johji Inazawa,
- Ikuo Nobuhisa,
- Tetsushi Kagawa,
- Tetsuya Taga,
- Mohamed Darwish,
- Hirofumi Nishizono,
- Keizo Takao,
- Kiran Sapkota,
- Kazutoshi Nakazawa,
- Tsuyoshi Takagi,
- Haruki Fujisawa,
- Yoshihisa Sugimura,
- Kyosuke Yamanishi,
- Lakshmi Rajagopal,
- Nanette Deneen Hannah,
- Herbert Y Meltzer,
- Tohru Yamamoto,
- Shuji Wakatsuki,
- Toshiyuki Araki,
- Katsuhiko Tabuchi,
- Tadahiro Numakawa,
- Hiroshi Kunugi,
- Freesia L Huang,
- Atsuko Hayata-Takano,
- Hitoshi Hashimoto,
- Kota Tamada,
- Toru Takumi,
- Takaoki Kasahara,
- Tadafumi Kato,
- Isabella A Graef,
- Gerald R Crabtree,
- Nozomi Asaoka,
- Hikari Hatakama,
- Shuji Kaneko,
- Takao Kohno,
- Mitsuharu Hattori,
- Yoshio Hoshiba,
- Ryuhei Miyake,
- Kisho Obi-Nagata,
- Akiko Hayashi-Takagi,
- Léa J Becker,
- Ipek Yalcin,
- Yoko Hagino,
- Hiroko Kotajima-Murakami,
- Yuki Moriya,
- Kazutaka Ikeda,
- Hyopil Kim,
- Bong-Kiun Kaang,
- Hikari Otabi,
- Yuta Yoshida,
- Atsushi Toyoda,
- Noboru H Komiyama,
- Seth GN Grant,
- Michiru Ida-Eto,
- Masaaki Narita,
- Ken-ichi Matsumoto,
- Emiko Okuda-Ashitaka,
- Iori Ohmori,
- Tadayuki Shimada,
- Kanato Yamagata,
- Hiroshi Ageta,
- Kunihiro Tsuchida,
- Kaoru Inokuchi,
- Takayuki Sassa,
- Akio Kihara,
- Motoaki Fukasawa,
- Nobuteru Usuda,
- Tayo Katano,
- Teruyuki Tanaka,
- Yoshihiro Yoshihara,
- Michihiro Igarashi,
- Takashi Hayashi,
- Kaori Ishikawa,
- Satoshi Yamamoto,
- Naoya Nishimura,
- Kazuto Nakada,
- Shinji Hirotsune,
- Kiyoshi Egawa,
- Kazuma Higashisaka,
- Yasuo Tsutsumi,
- Shoko Nishihara,
- Noriyuki Sugo,
- Takeshi Yagi,
- Naoto Ueno,
- Tomomi Yamamoto,
- Yoshihiro Kubo,
- Rie Ohashi,
- Nobuyuki Shiina,
- Kimiko Shimizu,
- Sayaka Higo-Yamamoto,
- Katsutaka Oishi,
- Hisashi Mori,
- Tamio Furuse,
- Masaru Tamura,
- Hisashi Shirakawa,
- Daiki X Sato,
- Yukiko U Inoue,
- Takayoshi Inoue,
- Yuriko Komine,
- Tetsuo Yamamori,
- Kenji Sakimura,
- Tsuyoshi Miyakawa
Affiliations
- Hideo Hagihara
- ORCiD
- Division of Systems Medical Science, Center for Medical Science, Fujita Health University, Toyoake, Japan
- Hirotaka Shoji
- Division of Systems Medical Science, Center for Medical Science, Fujita Health University, Toyoake, Japan
- Satoko Hattori
- Division of Systems Medical Science, Center for Medical Science, Fujita Health University, Toyoake, Japan
- Giovanni Sala
- Division of Systems Medical Science, Center for Medical Science, Fujita Health University, Toyoake, Japan
- Yoshihiro Takamiya
- Division of Systems Medical Science, Center for Medical Science, Fujita Health University, Toyoake, Japan
- Mika Tanaka
- Division of Systems Medical Science, Center for Medical Science, Fujita Health University, Toyoake, Japan
- Masafumi Ihara
- Department of Neurology, National Cerebral and Cardiovascular Center, Suita, Japan
- Mihiro Shibutani
- Laboratory of Genome Science, Biosignal Genome Resource Center, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Japan
- Izuho Hatada
- Laboratory of Genome Science, Biosignal Genome Resource Center, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Japan
- Kei Hori
- Department of Biochemistry and Cellular Biology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Japan
- Mikio Hoshino
- ORCiD
- Department of Biochemistry and Cellular Biology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Japan
- Akito Nakao
- ORCiD
- Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Kyoto, Japan
- Yasuo Mori
- Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Kyoto, Japan
- Shigeo Okabe
- ORCiD
- Department of Cellular Neurobiology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
- Masayuki Matsushita
- Department of Molecular Cellular Physiology, Graduate School of Medicine, University of the Ryukyus, Nishihara, Japan
- Anja Urbach
- Department of Neurology, Jena University Hospital, Jena, Germany
- Yuta Katayama
- Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
- Akinobu Matsumoto
- Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
- Keiichi I Nakayama
- Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
- Shota Katori
- Laboratory of Mammalian Neural Circuits, National Institute of Genetics, Mishima, Japan
- Takuya Sato
- Laboratory of Mammalian Neural Circuits, National Institute of Genetics, Mishima, Japan
- Takuji Iwasato
- Laboratory of Mammalian Neural Circuits, National Institute of Genetics, Mishima, Japan
- Haruko Nakamura
- Department of Molecular Pharmacology and Neurobiology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
- Yoshio Goshima
- Department of Molecular Pharmacology and Neurobiology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
- Matthieu Raveau
- Laboratory for Neurogenetics, RIKEN Center for Brain Science, Wako, Japan
- Tetsuya Tatsukawa
- Laboratory for Neurogenetics, RIKEN Center for Brain Science, Wako, Japan
- Kazuhiro Yamakawa
- ORCiD
- Laboratory for Neurogenetics, RIKEN Center for Brain Science, Wako, Japan; Department of Neurodevelopmental Disorder Genetics, Institute of Brain Sciences, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
- Noriko Takahashi
- Laboratory of Structural Physiology, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo, Japan; Department of Physiology, Kitasato University School of Medicine, Sagamihara, Japan
- Haruo Kasai
- ORCiD
- Laboratory of Structural Physiology, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo, Japan; International Research Center for Neurointelligence (WPI-IRCN), UTIAS, The University of Tokyo, Tokyo, Japan
- Johji Inazawa
- Research Core, Tokyo Medical and Dental University, Tokyo, Japan
- Ikuo Nobuhisa
- Department of Stem Cell Regulation, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan
- Tetsushi Kagawa
- Department of Stem Cell Regulation, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan
- Tetsuya Taga
- Department of Stem Cell Regulation, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan
- Mohamed Darwish
- Department of Biochemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt; Department of Behavioral Physiology, Graduate School of Innovative Life Science, University of Toyama, Toyama, Japan
- Hirofumi Nishizono
- Medical Research Institute, Kanazawa Medical University, Kahoku, Japan
- Keizo Takao
- ORCiD
- Department of Behavioral Physiology, Graduate School of Innovative Life Science, University of Toyama, Toyama, Japan; Department of Behavioral Physiology, Faculty of Medicine, University of Toyama, Toyama, Japan
- Kiran Sapkota
- Department of Neuroscience, Southern Research, Birmingham, United States
- Kazutoshi Nakazawa
- Department of Neuroscience, Southern Research, Birmingham, United States
- Tsuyoshi Takagi
- Institute for Developmental Research, Aichi Developmental Disability Center, Kasugai, Japan
- Haruki Fujisawa
- Department of Endocrinology, Diabetes and Metabolism, School of Medicine, Fujita Health University, Toyoake, Japan
- Yoshihisa Sugimura
- Department of Endocrinology, Diabetes and Metabolism, School of Medicine, Fujita Health University, Toyoake, Japan
- Kyosuke Yamanishi
- ORCiD
- Department of Neuropsychiatry, Hyogo Medical University School of Medicine, Nishinomiya, Japan
- Lakshmi Rajagopal
- Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, United States
- Nanette Deneen Hannah
- Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, United States
- Herbert Y Meltzer
- Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, United States
- Tohru Yamamoto
- ORCiD
- Department of Molecular Neurobiology, Faculty of Medicine, Kagawa University, Kita-gun, Japan
- Shuji Wakatsuki
- Department of Peripheral Nervous System Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan
- Toshiyuki Araki
- Department of Peripheral Nervous System Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan
- Katsuhiko Tabuchi
- Department of Molecular & Cellular Physiology, Shinshu University School of Medicine, Matsumoto, Japan
- Tadahiro Numakawa
- Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Japan
- Hiroshi Kunugi
- Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Japan; Department of Psychiatry, Teikyo University School of Medicine, Tokyo, Japan
- Freesia L Huang
- Program of Developmental Neurobiology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, United States
- Atsuko Hayata-Takano
- Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Japan; Department of Pharmacology, Graduate School of Dentistry, Osaka University, Suita, Japan; United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University and University of Fukui, Suita, Japan
- Hitoshi Hashimoto
- ORCiD
- Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Japan; United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University and University of Fukui, Suita, Japan; Division of Bioscience, Institute for Datability Science, Osaka University, Suita, Japan; Transdimensional Life Imaging Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Suita, Japan; Department of Molecular Pharmaceutical Science, Graduate School of Medicine, Osaka University, Suita, Japan
- Kota Tamada
- ORCiD
- RIKEN Brain Science Institute, Wako, Japan; Department of Physiology and Cell Biology, Kobe University School of Medicine, Kobe, Japan
- Toru Takumi
- ORCiD
- RIKEN Brain Science Institute, Wako, Japan; Department of Physiology and Cell Biology, Kobe University School of Medicine, Kobe, Japan
- Takaoki Kasahara
- ORCiD
- Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Center for Brain Science, Wako, Japan; Institute of Biology and Environmental Sciences, Carl von Ossietzky University of Oldenburg, Oldenburg, Germany
- Tadafumi Kato
- Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Center for Brain Science, Wako, Japan; Department of Psychiatry and Behavioral Science, Juntendo University Graduate School of Medicine, Tokyo, Japan
- Isabella A Graef
- Department of Pathology, Stanford University School of Medicine, Stanford, United States
- Gerald R Crabtree
- Department of Pathology, Stanford University School of Medicine, Stanford, United States
- Nozomi Asaoka
- Department of Pharmacology, Kyoto Prefectural University of Medicine, Kyoto, Japan
- Hikari Hatakama
- Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan
- Shuji Kaneko
- Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan
- Takao Kohno
- ORCiD
- Department of Biomedical Science, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan
- Mitsuharu Hattori
- Department of Biomedical Science, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan
- Yoshio Hoshiba
- Laboratory of Medical Neuroscience, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Japan
- Ryuhei Miyake
- Laboratory for Multi-scale Biological Psychiatry, RIKEN Center for Brain Science, Wako, Japan
- Kisho Obi-Nagata
- Laboratory for Multi-scale Biological Psychiatry, RIKEN Center for Brain Science, Wako, Japan
- Akiko Hayashi-Takagi
- Laboratory of Medical Neuroscience, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Japan; Laboratory for Multi-scale Biological Psychiatry, RIKEN Center for Brain Science, Wako, Japan
- Léa J Becker
- Institut des Neurosciences Cellulaires et Intégratives, Centre National de la Recherche Scientifique, Université de Strasbourg, Strasbourg, France
- Ipek Yalcin
- Institut des Neurosciences Cellulaires et Intégratives, Centre National de la Recherche Scientifique, Université de Strasbourg, Strasbourg, France
- Yoko Hagino
- Addictive Substance Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
- Hiroko Kotajima-Murakami
- Addictive Substance Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
- Yuki Moriya
- Addictive Substance Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
- Kazutaka Ikeda
- Addictive Substance Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
- Hyopil Kim
- Department of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul, Republic of Korea; Department of Biomedical Engineering, Johns Hopkins School of Medicine, Baltimore, United States
- Bong-Kiun Kaang
- ORCiD
- Department of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul, Republic of Korea; Center for Cognition and Sociality, Institute for Basic Science (IBS), Daejeon, Republic of Korea
- Hikari Otabi
- College of Agriculture, Ibaraki University, Ami, Japan; United Graduate School of Agricultural Science, Tokyo University of Agriculture and Technology, Fuchu, Japan
- Yuta Yoshida
- College of Agriculture, Ibaraki University, Ami, Japan
- Atsushi Toyoda
- College of Agriculture, Ibaraki University, Ami, Japan; United Graduate School of Agricultural Science, Tokyo University of Agriculture and Technology, Fuchu, Japan; Ibaraki University Cooperation between Agriculture and Medical Science (IUCAM), Ibaraki, Japan
- Noboru H Komiyama
- Genes to Cognition Program, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom; Simons Initiative for the Developing Brain, Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom
- Seth GN Grant
- ORCiD
- Genes to Cognition Program, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom; Simons Initiative for the Developing Brain, Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom
- Michiru Ida-Eto
- Department of Developmental and Regenerative Medicine, Mie University, Graduate School of Medicine, Tsu, Japan
- Masaaki Narita
- Department of Developmental and Regenerative Medicine, Mie University, Graduate School of Medicine, Tsu, Japan
- Ken-ichi Matsumoto
- Department of Biosignaling and Radioisotope Experiment, Interdisciplinary Center for Science Research, Organization for Research and Academic Information, Shimane University, Izumo, Japan
- Emiko Okuda-Ashitaka
- Department of Biomedical Engineering, Osaka Institute of Technology, Osaka, Japan
- Iori Ohmori
- Department of Physiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
- Tadayuki Shimada
- ORCiD
- Child Brain Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
- Kanato Yamagata
- Child Brain Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
- Hiroshi Ageta
- Division for Therapies Against Intractable Diseases, Center for Medical Science, Fujita Health University, Toyoake, Japan
- Kunihiro Tsuchida
- ORCiD
- Division for Therapies Against Intractable Diseases, Center for Medical Science, Fujita Health University, Toyoake, Japan
- Kaoru Inokuchi
- ORCiD
- Research Center for Idling Brain Science, University of Toyama, Toyama, Japan; Department of Biochemistry, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan; Core Research for Evolutionary Science and Technology (CREST), Japan Science and Technology Agency (JST), University of Toyama, Toyama, Japan
- Takayuki Sassa
- ORCiD
- Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan
- Akio Kihara
- ORCiD
- Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan
- Motoaki Fukasawa
- Department of Anatomy II, Fujita Health University School of Medicine, Toyoake, Japan
- Nobuteru Usuda
- Department of Anatomy II, Fujita Health University School of Medicine, Toyoake, Japan
- Tayo Katano
- Department of Medical Chemistry, Kansai Medical University, Hirakata, Japan
- Teruyuki Tanaka
- Department of Developmental Medical Sciences, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
- Yoshihiro Yoshihara
- Laboratory for Systems Molecular Ethology, RIKEN Center for Brain Science, Wako, Japan
- Michihiro Igarashi
- ORCiD
- Department of Neurochemistry and Molecular Cell Biology, School of Medicine, and Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan; Transdiciplinary Research Program, Niigata University, Niigata, Japan
- Takashi Hayashi
- ORCiD
- Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Japan
- Kaori Ishikawa
- ORCiD
- Institute of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Japan; Graduate School of Science and Technology, University of Tsukuba, Tsukuba, Japan
- Satoshi Yamamoto
- Integrated Technology Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd, Fujisawa, Japan
- Naoya Nishimura
- Integrated Technology Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd, Fujisawa, Japan
- Kazuto Nakada
- Institute of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Japan; Graduate School of Science and Technology, University of Tsukuba, Tsukuba, Japan
- Shinji Hirotsune
- Department of Genetic Disease Research, Osaka City University Graduate School of Medicine, Osaka, Japan
- Kiyoshi Egawa
- Department of Pediatrics, Hokkaido University Graduate School of Medicine, Sapporo, Japan
- Kazuma Higashisaka
- Laboratory of Toxicology and Safety Science, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Japan
- Yasuo Tsutsumi
- Laboratory of Toxicology and Safety Science, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Japan
- Shoko Nishihara
- ORCiD
- Glycan & Life Systems Integration Center (GaLSIC), Soka University, Tokyo, Japan
- Noriyuki Sugo
- Graduate School of Frontier Biosciences, Osaka University, Suita, Japan
- Takeshi Yagi
- Graduate School of Frontier Biosciences, Osaka University, Suita, Japan
- Naoto Ueno
- ORCiD
- Laboratory of Morphogenesis, National Institute for Basic Biology, Okazaki, Japan
- Tomomi Yamamoto
- Division of Biophysics and Neurobiology, National Institute for Physiological Sciences, Okazaki, Japan
- Yoshihiro Kubo
- ORCiD
- Division of Biophysics and Neurobiology, National Institute for Physiological Sciences, Okazaki, Japan
- Rie Ohashi
- Laboratory of Neuronal Cell Biology, National Institute for Basic Biology, Okazaki, Japan; Department of Basic Biology, SOKENDAI (Graduate University for Advanced Studies), Okazaki, Japan; Exploratory Research Center on Life and Living Systems (ExCELLS), National Institutes of Natural Sciences, Okazaki, Japan
- Nobuyuki Shiina
- ORCiD
- Laboratory of Neuronal Cell Biology, National Institute for Basic Biology, Okazaki, Japan; Department of Basic Biology, SOKENDAI (Graduate University for Advanced Studies), Okazaki, Japan; Exploratory Research Center on Life and Living Systems (ExCELLS), National Institutes of Natural Sciences, Okazaki, Japan
- Kimiko Shimizu
- ORCiD
- Department of Biological Sciences, School of Science, The University of Tokyo, Tokyo, Japan
- Sayaka Higo-Yamamoto
- Healthy Food Science Research Group, Cellular and Molecular Biotechnology Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Japan
- Katsutaka Oishi
- ORCiD
- Healthy Food Science Research Group, Cellular and Molecular Biotechnology Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Japan; Department of Applied Biological Science, Graduate School of Science and Technology, Tokyo University of Science, Noda, Japan; Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Japan; School of Integrative and Global Majors (SIGMA), University of Tsukuba, Tsukuba, Japan
- Hisashi Mori
- ORCiD
- Department of Molecular Neuroscience, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan
- Tamio Furuse
- Mouse Phenotype Analysis Division, Japan Mouse Clinic, RIKEN BioResource Research Center (BRC), Tsukuba, Japan
- Masaru Tamura
- Mouse Phenotype Analysis Division, Japan Mouse Clinic, RIKEN BioResource Research Center (BRC), Tsukuba, Japan
- Hisashi Shirakawa
- ORCiD
- Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan
- Daiki X Sato
- ORCiD
- Division of Systems Medical Science, Center for Medical Science, Fujita Health University, Toyoake, Japan; Graduate School of Life Sciences, Tohoku University, Sendai, Japan
- Yukiko U Inoue
- ORCiD
- Department of Biochemistry and Cellular Biology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Japan
- Takayoshi Inoue
- Department of Biochemistry and Cellular Biology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Japan
- Yuriko Komine
- ORCiD
- Young Researcher Support Group, Research Enhancement Strategy Office, National Institute for Basic Biology, National Institute of Natural Sciences, Okazaki, Japan; Division of Brain Biology, National Institute for Basic Biology, Okazaki, Japan
- Tetsuo Yamamori
- Division of Brain Biology, National Institute for Basic Biology, Okazaki, Japan; Laboratory for Molecular Analysis of Higher Brain Function, RIKEN Center for Brain Science, Wako, Japan
- Kenji Sakimura
- ORCiD
- Department of Cellular Neurobiology, Brain Research Institute, Niigata University, Niigata, Japan; Department of Animal Model Development, Brain Research Institute, Niigata University, Niigata, Japan
- Tsuyoshi Miyakawa
- ORCiD
- Division of Systems Medical Science, Center for Medical Science, Fujita Health University, Toyoake, Japan
- DOI
- https://doi.org/10.7554/eLife.89376
- Journal volume & issue
-
Vol. 12
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.
Keywords
