Altered brain pH and lactate levels could play a key role in neuropsychiatric disorders

In a groundbreaking research effort, scientists across the globe have unveiled findings that connect the dots between brain energy metabolism dysfunctions and a spectrum of neuropsychiatric and neurodegenerative disorders including intellectual disability, autism spectrum disorders, schizophrenia, bipolar disorder, depressive disorders, and Alzheimer’s disease.

This massive collaborative effort, involving 131 scientists from 105 laboratories across seven countries, has pinpointed alterations in brain pH and lactate levels as key indicators of this metabolic dysfunction. Published in the journal eLife, the findings challenge long-standing theories and offer new avenues for diagnosing and treating these complex disorders.

Mental health disorders affect over a third of the population worldwide at some point in their lives, presenting a significant public health challenge. Despite their varied symptoms and diagnoses, these conditions often share common biological markers, including genetic mutations, molecular changes, and brain activity alterations. This similarity suggests a potential common biological underpinning.

Previous research has pointed to metabolic changes in the brain, such as elevated lactate levels, as a common thread in these disorders. Building on this premise, the international team of researchers sought to better understand the metabolic dysfunctions in the brain.

The researchers analyzed a vast array of animal models, encompassing mice, rats, and chicks, which collectively represented a spectrum of neuropsychiatric and neurodegenerative diseases. They discovered that shifts in brain pH and lactate levels were indeed prevalent across these models.

Approximately 30% of the animal models investigated—spanning a total of 109 types—showed significant alterations in brain pH and lactate levels. This finding underscores a common pathological thread across a multitude of neuropsychiatric conditions, suggesting that disruptions in brain energy metabolism are a widespread phenomenon.

Such metabolic changes, involving deviations in the normal levels of lactate (a key metabolic product) and pH (indicative of acidity), point towards a shared biological basis among these disorders, despite their clinical diversity.

Animal models designed to simulate depression through exposure to psychological stress, as well as models induced to develop diabetes or colitis (conditions known to have a high comorbidity with depression), demonstrated a consistent pattern of decreased brain pH and increased lactate levels. This suggests that not just genetic or inherent factors, but also acquired environmental conditions, can significantly impact brain metabolism, contributing to the pathophysiology of neuropsychiatric conditions.

By integrating data from behavioral tests, the researchers found a predominant correlation between elevated lactate levels in the brain and deficits in working memory performance. This connection illuminates how metabolic dysfunctions can directly affect cognitive processes, potentially leading to the cognitive impairments observed in various neuropsychiatric disorders.

Finally, the study highlights the metabolic complexity inherent within the autism spectrum. The variable responses observed in autism models—some showing an increase in pH and a decrease in lactate levels—suggest the presence of diverse subpopulations within the spectrum. This variability points to the metabolic heterogeneity among individuals with autism spectrum disorders, indicating that different subgroups may have distinct metabolic dysfunctions.

“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,” explained Hideo Hagihara of Fujita Health University, the study’s lead author.

Despite these significant insights, the study is not without its limitations. The broad scope of animal models and diseases covered means that the findings, while compelling, require further specification to understand the exact mechanisms at play in humans. Additionally, the reliance on animal models means that the direct applicability of the results to human conditions needs further validation.

Looking ahead, the researchers are keen on extending their findings to more nuanced studies that could dissect the regional and cellular specificity of the observed metabolic changes in the brain. Such detailed investigations could pave the way for targeted therapeutic strategies that address the metabolic underpinnings of these disorders.

“This research could be a stepping stone towards identifying shared therapeutic targets in various neuropsychiatric disorders,” said co-author Tsuyoshi Miyakawa. “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.”

The study, “Large-scale animal model study uncovers altered brain pH and lactate levels as a transdiagnostic endophenotype of neuropsychiatric disorders involving cognitive impairment,” was authored by 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 G. N. 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, and Tsuyoshi Miyakawa.