Large-scale animal model study uncovers altered brain pH and lactate levels as a transdiagnostic endophenotype of neuropsychiatric disorders involving cognitive impairment
Authors: Hagihara Hideo , Shoji Hirotaka , Hattori Satoko , Sala Giovanni , Takamiya Yoshihiro , Tanaka Mika , Ihara Masafumi , Shibutani Mihiro , Hatada Izuho , Hori Kei , Hoshino Mikio , Nakao Akito , Mori Yasuo , Okabe Shigeo , Matsushita Masayuki , Urbach Anja , Katayama Yuta , Matsumoto Akinobu , Nakayama Keiichi I. , Katori Shota , Sato Takuya , Iwasato Takuji , Nakamura Haruko , Goshima Yoshio , Raveau Matthieu , Tatsukawa Tetsuya , Yamakawa Kazuhiro , Takahashi Noriko , Kasai Haruo , Inazawa Johji , Nobuhisa Ikuo , Kagawa Tetsushi , Taga Tetsuya , Darwish Mohamed , Nishizono Hirofumi , Takao Keizo , Sapkota Kiran , Nakazawa Kazutoshi , Takagi Tsuyoshi , Fujisawa Haruki , Sugimura Yoshihisa , Yamanishi Kyosuke , Rajagopal Lakshmi , Hannah Nanette Deneen , Meltzer Herbert Y. , Yamamoto Tohru , Wakatsuki Shuji , Araki Toshiyuki , Tabuchi Katsuhiko , Numakawa Tadahiro , Kunugi Hiroshi , Huang Freesia L. , Hayata-Takano Atsuko , Hashimoto Hitoshi , Tamada Kota , Takumi Toru , Kasahara Takaoki , Kato Tadafumi , Graef Isabella A. , Crabtree Gerald R. , Asaoka Nozomi , Hatakama Hikari , Kaneko Shuji , Kohno Takao , Hattori Mitsuharu , Hoshiba Yoshio , Miyake Ryuhei , Obi-Nagata Kisho , Hayashi-Takagi Akiko , Becker Léa J. , Yalcin Ipek , Hagino Yoko , Kotajima-Murakami Hiroko , Moriya Yuki , Ikeda Kazutaka , Kim Hyopil , Kaang Bong-Kiun , Otabi Hikari , Yoshida Yuta , Toyoda Atsushi , Komiyama Noboru H. , Grant Seth G. N. , Ida-Eto Michiru , Narita Masaaki , Matsumoto Ken-ichi , Okuda-Ashitaka Emiko , Ohmori Iori , Shimada Tadayuki , Yamagata Kanato , Ageta Hiroshi , Tsuchida Kunihiro , Inokuchi Kaoru , Sassa Takayuki , Kihara Akio , Fukasawa Motoaki , Usuda Nobuteru , Katano Tayo , Tanaka Teruyuki , Yoshihara Yoshihiro , Igarashi Michihiro , Hayashi Takashi , Ishikawa Kaori , Yamamoto Satoshi , Nishimura Naoya , Nakada Kazuto , Hirotsune Shinji , Egawa Kiyoshi , Higashisaka Kazuma , Tsutsumi Yasuo , Nishihara Shoko , Sugo Noriyuki , Yagi Takeshi , Ueno Naoto , Yamamoto Tomomi , Kubo Yoshihiro , Ohashi Rie , Shiina Nobuyuki , Shimizu Kimiko , Higo-Yamamoto Sayaka , Oishi Katsutaka , Mori Hisashi , Furuse Tamio , Tamura Masaru , Shirakawa Hisashi , Sato Daiki X. , Inoue Yukiko U. , Inoue Takayoshi , Komine Yuriko , Yamamori Tetsuo , Sakimura Kenji , Miyakawa Tsuyoshi 
Published: September 2023

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 2,294 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.