Large-scale animal model study uncovers altered brain pH and lactate levels as a transdiagnostic endophenotype of neuropsychiatric disorders involving cognitive impairment
2024
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
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.
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