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 Hagihara 1 , Hirotaka Shoji 1 , Satoko Hattori 1 , Giovanni Sala 1 , Yoshihiro Takamiya 1 , Mika Tanaka 1 , Masafumi Ihara 2 , Mihiro Shibutani 3 , Izuho Hatada 3 , Kei Hori 4 , Mikio Hoshino 4 , Akito Nakao 5 , Yasuo Mori 5 , Shigeo Okabe 6 , Masayuki Matsushita 7 , Anja Urbach 8 , Yuta Katayama 9 , Akinobu Matsumoto 9 , Keiichi I. Nakayama 9 , Shota Katori 10 , Takuya Sato 10 , Takuji Iwasato 10 , Haruko Nakamura 11 , Yoshio Goshima 11 , Matthieu Raveau 12 , Tetsuya Tatsukawa 12 , Kazuhiro Yamakawa 12, 13 , Noriko Takahashi 14, 15 , Haruo Kasai 14, 16 , Johji Inazawa 17 , Ikuo Nobuhisa 18 , Tetsushi Kagawa 18 , Tetsuya Taga 18 , Mohamed Darwish 19, 20 , Hirofumi Nishizono 21 , Keizo Takao 20, 22 , Kiran Sapkota 23 , Kazutoshi Nakazawa 23 , Tsuyoshi Takagi 24 , Haruki Fujisawa 25 , Yoshihisa Sugimura 25 , Kyosuke Yamanishi 26 , Lakshmi Rajagopal 27 , Nanette Deneen Hannah 27 , Herbert Y. Meltzer 27 , Tohru Yamamoto 28 , Shuji Wakatsuki 29 , Toshiyuki Araki 29 , Katsuhiko Tabuchi 30 , Tadahiro Numakawa 31 , Hiroshi Kunugi 31, 32 , Freesia L. Huang 33 , 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. Graef 45 , Gerald R. Crabtree 45 , Nozomi Asaoka 46 , Hikari Hatakama 47 , Shuji Kaneko 47 , Takao Kohno 48 , Mitsuharu Hattori 48 , Yoshio Hoshiba 49 , Ryuhei Miyake 50 , Kisho Obi-Nagata 50 , Akiko Hayashi-Takagi 49, 50 , Léa J. Becker 51 , Ipek Yalcin 51 , Yoko Hagino 52 , Hiroko Kotajima-Murakami 52 , Yuki Moriya 52 , Kazutaka Ikeda 52 , Hyopil Kim 53, 54 , Bong-Kiun Kaang 53, 55 , Hikari Otabi 56, 57 , Yuta Yoshida 56 , Atsushi Toyoda 56-58 , Noboru H. Komiyama 59, 60 , Seth G. N. Grant 59, 60 , Michiru Ida-Eto 61 , Masaaki Narita 61 , Ken-ichi Matsumoto 62 , Emiko Okuda-Ashitaka 63 , Iori Ohmori 64 , Tadayuki Shimada 65 , Kanato Yamagata 65 , Hiroshi Ageta 66 , Kunihiro Tsuchida 66 , Kaoru Inokuchi 67-69 , Takayuki Sassa 70 , Akio Kihara 70 , Motoaki Fukasawa 71 , Nobuteru Usuda 71 , Tayo Katano 72 , Teruyuki Tanaka 73 , Yoshihiro Yoshihara 74 , Michihiro Igarashi 75, 76 , Takashi Hayashi 77 , Kaori Ishikawa 78, 79 , Satoshi Yamamoto 80 , Naoya Nishimura 80 , Kazuto Nakada 78, 79 , Shinji Hirotsune 81 , Kiyoshi Egawa 82 , Kazuma Higashisaka 83 , Yasuo Tsutsumi 83 , Shoko Nishihara 84 , Noriyuki Sugo 85 , Takeshi Yagi 85 , Naoto Ueno 86 , Tomomi Yamamoto 87 , Yoshihiro Kubo 87 , Rie Ohashi 88-90 , Nobuyuki Shiina 88-90 , Kimiko Shimizu 91 , Sayaka Higo-Yamamoto 92 , Katsutaka Oishi 92-95 , Hisashi Mori 96 , Tamio Furuse 97 , Masaru Tamura 97 , Hisashi Shirakawa 98 , Daiki X. Sato 1, 99 , Yukiko U. Inoue 100 , Takayoshi Inoue 100 , Yuriko Komine 101, 102 , Tetsuo Yamamori 102, 103 , Kenji Sakimura 104, 105 , Tsuyoshi Miyakawa 1
Affiliations
eLife
Data/statistical analysis
Animal tissue samples
Large-scale animal model study uncovers altered brain pH and lactate levels as a transdiagnostic endophenotype of neuropsychiatric disorders involving cognitive impairment
26-Mar-2024