Large-scale animal model study uncovers altered brain pH and lactate levels as a transdiagnostic endophenotype of neuropsychiatric disorders involving cognitive impairment.
Journal: eLife
Volume: 12
Issue:
Year of Publication: 2024
Affiliated Institutions:
Division of Systems Medical Science, Center for Medical Science, Fujita Health University, Toyoake, Japan.
Department of Neurology, National Cerebral and Cardiovascular Center, Suita, Japan.
Laboratory of Genome Science, Biosignal Genome Resource Center, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Japan.
Department of Biochemistry and Cellular Biology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Japan.
Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Kyoto, Japan.
Department of Cellular Neurobiology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Department of Molecular Cellular Physiology, Graduate School of Medicine, University of the Ryukyus, Nishihara, Japan.
Department of Neurology, Jena University Hospital, Jena, Germany.
Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
Laboratory of Mammalian Neural Circuits, National Institute of Genetics, Mishima, Japan.
Department of Molecular Pharmacology and Neurobiology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
Laboratory for Neurogenetics, RIKEN Center for Brain Science, Wako, Japan.
Laboratory of Structural Physiology, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
Research Core, Tokyo Medical and Dental University, Tokyo, Japan.
Department of Stem Cell Regulation, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
Department of Biochemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
Medical Research Institute, Kanazawa Medical University, Kahoku, Japan.
Department of Behavioral Physiology, Graduate School of Innovative Life Science, University of Toyama, Toyama, Japan.
Department of Neuroscience, Southern Research, Birmingham, United States.
Institute for Developmental Research, Aichi Developmental Disability Center, Kasugai, Japan.
Department of Endocrinology, Diabetes and Metabolism, School of Medicine, Fujita Health University, Toyoake, Japan.
Department of Neuropsychiatry, Hyogo Medical University School of Medicine, Nishinomiya, Japan.
Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, United States.
Department of Molecular Neurobiology, Faculty of Medicine, Kagawa University, Kita-gun, Japan.
Department of Peripheral Nervous System Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.
Department of Molecular & Cellular Physiology, Shinshu University School of Medicine, Matsumoto, Japan.
Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Japan.
Program of Developmental Neurobiology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, United States.
Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Japan.
RIKEN Brain Science Institute, Wako, Japan.
Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Center for Brain Science, Wako, Japan.
Department of Pathology, Stanford University School of Medicine, Stanford, United States.
Department of Pharmacology, Kyoto Prefectural University of Medicine, Kyoto, Japan.
Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan.
Department of Biomedical Science, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan.
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.
Institut des Neurosciences Cellulaires et Intégratives, Centre National de la Recherche Scientifique, Université de Strasbourg, Strasbourg, France.
Addictive Substance Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
Department of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul, Republic of Korea.
College of Agriculture, Ibaraki University, Ami, Japan.
Genes to Cognition Program, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom.
Department of Developmental and Regenerative Medicine, Mie University, Graduate School of Medicine, Tsu, Japan.
Department of Biosignaling and Radioisotope Experiment, Interdisciplinary Center for Science Research, Organization for Research and Academic Information, Shimane University, Izumo, Japan.
Department of Biomedical Engineering, Osaka Institute of Technology, Osaka, Japan.
Department of Physiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
Child Brain Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
Division for Therapies Against Intractable Diseases, Center for Medical Science, Fujita Health University, Toyoake, Japan.
Research Center for Idling Brain Science, University of Toyama, Toyama, Japan.
Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
Department of Anatomy II, Fujita Health University School of Medicine, Toyoake, Japan.
Department of Medical Chemistry, Kansai Medical University, Hirakata, Japan.
Department of Developmental Medical Sciences, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Laboratory for Systems Molecular Ethology, RIKEN Center for Brain Science, Wako, Japan.
Department of Neurochemistry and Molecular Cell Biology, School of Medicine, and Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan.
Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Japan.
Institute of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Japan.
Integrated Technology Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd, Fujisawa, Japan.
Department of Genetic Disease Research, Osaka City University Graduate School of Medicine, Osaka, Japan.
Department of Pediatrics, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Laboratory of Toxicology and Safety Science, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Japan.
Glycan & Life Systems Integration Center (GaLSIC), Soka University, Tokyo, Japan.
Graduate School of Frontier Biosciences, Osaka University, Suita, Japan.
Laboratory of Morphogenesis, National Institute for Basic Biology, Okazaki, Japan.
Division of Biophysics and Neurobiology, National Institute for Physiological Sciences, Okazaki, Japan.
Laboratory of Neuronal Cell Biology, National Institute for Basic Biology, Okazaki, Japan.
Department of Biological Sciences, School of Science, The University of Tokyo, Tokyo, Japan.
Healthy Food Science Research Group, Cellular and Molecular Biotechnology Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Japan.
Department of Molecular Neuroscience, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
Mouse Phenotype Analysis Division, Japan Mouse Clinic, RIKEN BioResource Research Center (BRC), Tsukuba, Japan.
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.
Department of Cellular Neurobiology, Brain Research Institute, Niigata University, Niigata, Japan.
Abstract summary
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.
Authors & Co-authors:
Hagihara
Shoji
Hattori
Sala
Takamiya
Tanaka
Ihara
Shibutani
Hatada
Hori
Hoshino
Nakao
Mori
Okabe
Matsushita
Urbach
Katayama
Matsumoto
Nakayama
Katori
Sato
Iwasato
Nakamura
Goshima
Raveau
Tatsukawa
Yamakawa
Takahashi
Kasai
Inazawa
Nobuhisa
Kagawa
Taga
Darwish
Nishizono
Takao
Sapkota
Nakazawa
Takagi
Fujisawa
Sugimura
Yamanishi
Rajagopal
Hannah
Meltzer
Yamamoto
Wakatsuki
Araki
Tabuchi
Numakawa
Kunugi
Huang
Hayata-Takano
Hashimoto
Tamada
Takumi
Kasahara
Kato
Graef
Crabtree
Asaoka
Hatakama
Kaneko
Kohno
Hattori
Hoshiba
Miyake
Obi-Nagata
Hayashi-Takagi
Becker
Yalcin
Hagino
Kotajima-Murakami
Moriya
Ikeda
Kim
Kaang
Otabi
Yoshida
Toyoda
Komiyama
Grant
Ida-Eto
Narita
Matsumoto
Okuda-Ashitaka
Ohmori
Shimada
Yamagata
Ageta
Tsuchida
Inokuchi
Sassa
Kihara
Fukasawa
Usuda
Katano
Tanaka
Yoshihara
Igarashi
Hayashi
Ishikawa
Yamamoto
Nishimura
Nakada
Hirotsune
Egawa
Higashisaka
Tsutsumi
Nishihara
Sugo
Yagi
Ueno
Yamamoto
Kubo
Ohashi
Shiina
Shimizu
Higo-Yamamoto
Oishi
Mori
Furuse
Tamura
Shirakawa
Sato
Inoue
Inoue
Komine
Yamamori
Sakimura
Miyakawa
Study Outcome
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