Large-scale animal model study uncovers altered brain pH and lactate levels as a transdiagnostic endophenotype of neuropsychiatric disorders involving cognitive impairment
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 disord...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
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eLife Sciences Publications Ltd
2024-03-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/89376 |
| _version_ | 1797244678747193344 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Hideo Hagihara |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-24T19:14:50Z |
| format | Article |
| id | doaj.art-15de117935204a21a8487997042e8094 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-24T19:14:50Z |
| publishDate | 2024-03-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-15de117935204a21a8487997042e80942024-03-26T07:30:24ZengeLife Sciences Publications LtdeLife2050-084X2024-03-011210.7554/eLife.89376Large-scale animal model study uncovers altered brain pH and lactate levels as a transdiagnostic endophenotype of neuropsychiatric disorders involving cognitive impairmentHideo Hagihara0https://orcid.org/0000-0001-9602-9518Hirotaka Shoji1Satoko Hattori2Giovanni Sala3Yoshihiro Takamiya4Mika Tanaka5Masafumi Ihara6Mihiro Shibutani7Izuho Hatada8Kei Hori9Mikio Hoshino10https://orcid.org/0000-0002-9526-3473Akito Nakao11https://orcid.org/0000-0002-2296-8245Yasuo Mori12Shigeo Okabe13https://orcid.org/0000-0003-1216-8890Masayuki Matsushita14Anja Urbach15Yuta Katayama16Akinobu Matsumoto17Keiichi I Nakayama18Shota Katori19Takuya Sato20Takuji Iwasato21Haruko Nakamura22Yoshio Goshima23Matthieu Raveau24Tetsuya Tatsukawa25Kazuhiro Yamakawa26https://orcid.org/0000-0002-1478-4390Noriko Takahashi27Haruo Kasai28https://orcid.org/0000-0003-2327-9027Johji Inazawa29Ikuo Nobuhisa30Tetsushi Kagawa31Tetsuya Taga32Mohamed Darwish33Hirofumi Nishizono34Keizo Takao35https://orcid.org/0000-0002-4734-3583Kiran Sapkota36Kazutoshi Nakazawa37Tsuyoshi Takagi38Haruki Fujisawa39Yoshihisa Sugimura40Kyosuke Yamanishi41https://orcid.org/0000-0001-5130-8193Lakshmi Rajagopal42Nanette Deneen Hannah43Herbert Y Meltzer44Tohru Yamamoto45https://orcid.org/0000-0002-1652-0233Shuji Wakatsuki46Toshiyuki Araki47Katsuhiko Tabuchi48Tadahiro Numakawa49Hiroshi Kunugi50Freesia L Huang51Atsuko Hayata-Takano52Hitoshi Hashimoto53https://orcid.org/0000-0001-6548-4016Kota Tamada54https://orcid.org/0000-0002-6575-6189Toru Takumi55https://orcid.org/0000-0001-7153-266XTakaoki Kasahara56https://orcid.org/0000-0002-0953-5146Tadafumi Kato57Isabella A Graef58Gerald R Crabtree59Nozomi Asaoka60Hikari Hatakama61Shuji Kaneko62Takao Kohno63https://orcid.org/0000-0003-2557-4281Mitsuharu Hattori64Yoshio Hoshiba65Ryuhei Miyake66Kisho Obi-Nagata67Akiko Hayashi-Takagi68Léa J Becker69Ipek Yalcin70Yoko Hagino71Hiroko Kotajima-Murakami72Yuki Moriya73Kazutaka Ikeda74Hyopil Kim75Bong-Kiun Kaang76https://orcid.org/0000-0001-7593-9707Hikari Otabi77Yuta Yoshida78Atsushi Toyoda79Noboru H Komiyama80Seth GN Grant81https://orcid.org/0000-0001-8732-8735Michiru Ida-Eto82Masaaki Narita83Ken-ichi Matsumoto84Emiko Okuda-Ashitaka85Iori Ohmori86Tadayuki Shimada87https://orcid.org/0000-0001-7333-9847Kanato Yamagata88Hiroshi Ageta89Kunihiro Tsuchida90https://orcid.org/0000-0002-3983-5756Kaoru Inokuchi91https://orcid.org/0000-0002-5393-3133Takayuki Sassa92https://orcid.org/0000-0003-3145-9829Akio Kihara93https://orcid.org/0000-0001-5889-0788Motoaki Fukasawa94Nobuteru Usuda95Tayo Katano96Teruyuki Tanaka97Yoshihiro Yoshihara98Michihiro Igarashi99https://orcid.org/0000-0003-1474-3385Takashi Hayashi100https://orcid.org/0000-0003-3591-2109Kaori Ishikawa101https://orcid.org/0000-0001-9895-5996Satoshi Yamamoto102Naoya Nishimura103Kazuto Nakada104Shinji Hirotsune105Kiyoshi Egawa106Kazuma Higashisaka107Yasuo Tsutsumi108Shoko Nishihara109https://orcid.org/0000-0002-1668-2603Noriyuki Sugo110Takeshi Yagi111Naoto Ueno112https://orcid.org/0000-0002-8375-2317Tomomi Yamamoto113Yoshihiro Kubo114https://orcid.org/0000-0001-6707-0837Rie Ohashi115Nobuyuki Shiina116https://orcid.org/0000-0002-1854-4239Kimiko Shimizu117https://orcid.org/0000-0003-4943-2552Sayaka Higo-Yamamoto118Katsutaka Oishi119https://orcid.org/0000-0002-4870-0837Hisashi Mori120https://orcid.org/0000-0001-9743-2456Tamio Furuse121Masaru Tamura122Hisashi Shirakawa123https://orcid.org/0000-0002-4129-0978Daiki X Sato124https://orcid.org/0000-0002-9527-8253Yukiko U Inoue125https://orcid.org/0000-0002-4105-9127Takayoshi Inoue126Yuriko Komine127https://orcid.org/0000-0002-0097-8813Tetsuo Yamamori128Kenji Sakimura129https://orcid.org/0000-0002-8091-8879Tsuyoshi Miyakawa130https://orcid.org/0000-0003-0137-8200Division of Systems Medical Science, Center for Medical Science, Fujita Health University, Toyoake, JapanDivision of Systems Medical Science, Center for Medical Science, Fujita Health University, Toyoake, JapanDivision of Systems Medical Science, Center for Medical Science, Fujita Health University, Toyoake, JapanDivision of Systems Medical Science, Center for Medical Science, Fujita Health University, Toyoake, JapanDivision of Systems Medical Science, Center for Medical Science, Fujita Health University, Toyoake, JapanDivision of Systems Medical Science, Center for Medical Science, Fujita Health University, Toyoake, JapanDepartment of Neurology, National Cerebral and Cardiovascular Center, Suita, JapanLaboratory of Genome Science, Biosignal Genome Resource Center, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, JapanLaboratory of Genome Science, Biosignal Genome Resource Center, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, JapanDepartment of Biochemistry and Cellular Biology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, JapanDepartment of Biochemistry and Cellular Biology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, JapanDepartment of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Kyoto, JapanDepartment of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Kyoto, JapanDepartment of Cellular Neurobiology, Graduate School of Medicine, The University of Tokyo, Tokyo, JapanDepartment of Molecular Cellular Physiology, Graduate School of Medicine, University of the Ryukyus, Nishihara, JapanDepartment of Neurology, Jena University Hospital, Jena, GermanyDepartment of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, JapanDepartment of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, JapanDepartment of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, JapanLaboratory of Mammalian Neural Circuits, National Institute of Genetics, Mishima, JapanLaboratory of Mammalian Neural Circuits, National Institute of Genetics, Mishima, JapanLaboratory of Mammalian Neural Circuits, National Institute of Genetics, Mishima, JapanDepartment of Molecular Pharmacology and Neurobiology, Yokohama City University Graduate School of Medicine, Yokohama, JapanDepartment of Molecular Pharmacology and Neurobiology, Yokohama City University Graduate School of Medicine, Yokohama, JapanLaboratory for Neurogenetics, RIKEN Center for Brain Science, Wako, JapanLaboratory for Neurogenetics, RIKEN Center for Brain Science, Wako, JapanLaboratory 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, JapanLaboratory 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, JapanLaboratory 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, JapanResearch Core, Tokyo Medical and Dental University, Tokyo, JapanDepartment of Stem Cell Regulation, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, JapanDepartment of Stem Cell Regulation, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, JapanDepartment of Stem Cell Regulation, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, JapanDepartment of Biochemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt; Department of Behavioral Physiology, Graduate School of Innovative Life Science, University of Toyama, Toyama, JapanMedical Research Institute, Kanazawa Medical University, Kahoku, JapanDepartment 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, JapanDepartment of Neuroscience, Southern Research, Birmingham, United StatesDepartment of Neuroscience, Southern Research, Birmingham, United StatesInstitute for Developmental Research, Aichi Developmental Disability Center, Kasugai, JapanDepartment of Endocrinology, Diabetes and Metabolism, School of Medicine, Fujita Health University, Toyoake, JapanDepartment of Endocrinology, Diabetes and Metabolism, School of Medicine, Fujita Health University, Toyoake, JapanDepartment of Neuropsychiatry, Hyogo Medical University School of Medicine, Nishinomiya, JapanDepartment of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, United StatesDepartment of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, United StatesDepartment of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, United StatesDepartment of Molecular Neurobiology, Faculty of Medicine, Kagawa University, Kita-gun, JapanDepartment of Peripheral Nervous System Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, JapanDepartment of Peripheral Nervous System Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, JapanDepartment of Molecular & Cellular Physiology, Shinshu University School of Medicine, Matsumoto, JapanDepartment of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, JapanDepartment 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, JapanProgram of Developmental Neurobiology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, United StatesLaboratory 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, JapanLaboratory 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, JapanRIKEN Brain Science Institute, Wako, Japan; Department of Physiology and Cell Biology, Kobe University School of Medicine, Kobe, JapanRIKEN Brain Science Institute, Wako, Japan; Department of Physiology and Cell Biology, Kobe University School of Medicine, Kobe, JapanLaboratory 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, GermanyLaboratory 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, JapanDepartment of Pathology, Stanford University School of Medicine, Stanford, United StatesDepartment of Pathology, Stanford University School of Medicine, Stanford, United StatesDepartment of Pharmacology, Kyoto Prefectural University of Medicine, Kyoto, JapanDepartment of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, JapanDepartment of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, JapanDepartment of Biomedical Science, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, JapanDepartment of Biomedical Science, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, JapanLaboratory of Medical Neuroscience, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, JapanLaboratory for Multi-scale Biological Psychiatry, RIKEN Center for Brain Science, Wako, JapanLaboratory for Multi-scale Biological Psychiatry, RIKEN Center for Brain Science, Wako, JapanLaboratory 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, JapanInstitut des Neurosciences Cellulaires et Intégratives, Centre National de la Recherche Scientifique, Université de Strasbourg, Strasbourg, FranceInstitut des Neurosciences Cellulaires et Intégratives, Centre National de la Recherche Scientifique, Université de Strasbourg, Strasbourg, FranceAddictive Substance Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, JapanAddictive Substance Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, JapanAddictive Substance Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, JapanAddictive Substance Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, JapanDepartment 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 StatesDepartment 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 KoreaCollege of Agriculture, Ibaraki University, Ami, Japan; United Graduate School of Agricultural Science, Tokyo University of Agriculture and Technology, Fuchu, JapanCollege of Agriculture, Ibaraki University, Ami, JapanCollege 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, JapanGenes 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 KingdomGenes 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 KingdomDepartment of Developmental and Regenerative Medicine, Mie University, Graduate School of Medicine, Tsu, JapanDepartment of Developmental and Regenerative Medicine, Mie University, Graduate School of Medicine, Tsu, JapanDepartment of Biosignaling and Radioisotope Experiment, Interdisciplinary Center for Science Research, Organization for Research and Academic Information, Shimane University, Izumo, JapanDepartment of Biomedical Engineering, Osaka Institute of Technology, Osaka, JapanDepartment of Physiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, JapanChild Brain Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, JapanChild Brain Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, JapanDivision for Therapies Against Intractable Diseases, Center for Medical Science, Fujita Health University, Toyoake, JapanDivision for Therapies Against Intractable Diseases, Center for Medical Science, Fujita Health University, Toyoake, JapanResearch 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, JapanFaculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, JapanFaculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, JapanDepartment of Anatomy II, Fujita Health University School of Medicine, Toyoake, JapanDepartment of Anatomy II, Fujita Health University School of Medicine, Toyoake, JapanDepartment of Medical Chemistry, Kansai Medical University, Hirakata, JapanDepartment of Developmental Medical Sciences, Graduate School of Medicine, The University of Tokyo, Tokyo, JapanLaboratory for Systems Molecular Ethology, RIKEN Center for Brain Science, Wako, JapanDepartment 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, JapanBiomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, JapanInstitute of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Japan; Graduate School of Science and Technology, University of Tsukuba, Tsukuba, JapanIntegrated Technology Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd, Fujisawa, JapanIntegrated Technology Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd, Fujisawa, JapanInstitute of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Japan; Graduate School of Science and Technology, University of Tsukuba, Tsukuba, JapanDepartment of Genetic Disease Research, Osaka City University Graduate School of Medicine, Osaka, JapanDepartment of Pediatrics, Hokkaido University Graduate School of Medicine, Sapporo, JapanLaboratory of Toxicology and Safety Science, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, JapanLaboratory of Toxicology and Safety Science, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, JapanGlycan & Life Systems Integration Center (GaLSIC), Soka University, Tokyo, JapanGraduate School of Frontier Biosciences, Osaka University, Suita, JapanGraduate School of Frontier Biosciences, Osaka University, Suita, JapanLaboratory of Morphogenesis, National Institute for Basic Biology, Okazaki, JapanDivision of Biophysics and Neurobiology, National Institute for Physiological Sciences, Okazaki, JapanDivision of Biophysics and Neurobiology, National Institute for Physiological Sciences, Okazaki, JapanLaboratory 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, JapanLaboratory 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, JapanDepartment of Biological Sciences, School of Science, The University of Tokyo, Tokyo, JapanHealthy Food Science Research Group, Cellular and Molecular Biotechnology Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, JapanHealthy 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, JapanDepartment of Molecular Neuroscience, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, JapanMouse Phenotype Analysis Division, Japan Mouse Clinic, RIKEN BioResource Research Center (BRC), Tsukuba, JapanMouse Phenotype Analysis Division, Japan Mouse Clinic, RIKEN BioResource Research Center (BRC), Tsukuba, JapanDepartment of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, JapanDivision of Systems Medical Science, Center for Medical Science, Fujita Health University, Toyoake, Japan; Graduate School of Life Sciences, Tohoku University, Sendai, JapanDepartment of Biochemistry and Cellular Biology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, JapanDepartment of Biochemistry and Cellular Biology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, JapanYoung 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, JapanDivision of Brain Biology, National Institute for Basic Biology, Okazaki, Japan; Laboratory for Molecular Analysis of Higher Brain Function, RIKEN Center for Brain Science, Wako, JapanDepartment of Cellular Neurobiology, Brain Research Institute, Niigata University, Niigata, Japan; Department of Animal Model Development, Brain Research Institute, Niigata University, Niigata, JapanDivision of Systems Medical Science, Center for Medical Science, Fujita Health University, Toyoake, JapanIncreased 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.https://elifesciences.org/articles/89376brain pHlactatemetabolismneuropsychiatric disordersanimal modelsworking memory |
| spellingShingle | 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 Large-scale animal model study uncovers altered brain pH and lactate levels as a transdiagnostic endophenotype of neuropsychiatric disorders involving cognitive impairment eLife brain pH lactate metabolism neuropsychiatric disorders animal models working memory |
| title | Large-scale animal model study uncovers altered brain pH and lactate levels as a transdiagnostic endophenotype of neuropsychiatric disorders involving cognitive impairment |
| title_full | Large-scale animal model study uncovers altered brain pH and lactate levels as a transdiagnostic endophenotype of neuropsychiatric disorders involving cognitive impairment |
| title_fullStr | Large-scale animal model study uncovers altered brain pH and lactate levels as a transdiagnostic endophenotype of neuropsychiatric disorders involving cognitive impairment |
| title_full_unstemmed | Large-scale animal model study uncovers altered brain pH and lactate levels as a transdiagnostic endophenotype of neuropsychiatric disorders involving cognitive impairment |
| title_short | Large-scale animal model study uncovers altered brain pH and lactate levels as a transdiagnostic endophenotype of neuropsychiatric disorders involving cognitive impairment |
| title_sort | large scale animal model study uncovers altered brain ph and lactate levels as a transdiagnostic endophenotype of neuropsychiatric disorders involving cognitive impairment |
| topic | brain pH lactate metabolism neuropsychiatric disorders animal models working memory |
| url | https://elifesciences.org/articles/89376 |
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