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Protein lactylation induced by neural excitation

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Hagihara, Hideo, Shoji, Hirotaka, Otabi, Hikari, Toyoda, Atsushi, Katoh, Kaoru, Namihira, Masakazu, Miyakawa, Tsuyoshi·2021·Cell Reports
DOI 10.1016/j.celrep.2021.109820

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Abstract

Abstract Lactate is known to have diverse roles in the brain at the molecular and behavioral levels under both physiological and pathophysiological conditions, such as learning and memory and regulation of mood. Recently, a novel post-translational modification called lysine lactylation has been found in histone H3 of mouse macrophages, and the lactylation levels paralleled the intracellular lactate levels 1 . However, it is unknown whether lysine lactylation occurs in brain cells, and if it does, whether lactylation is induced by the stimuli that accompany changes in lactate levels. Herein, we reveal that lysine lactylation in brain cells is regulated by systemic changes in lactate levels, neural excitation, and behaviorally relevant stimuli. Lysine lactylation levels were increased by lactate treatment and by high-potassium-induced depolarization in cultured primary neurons; these increases were attenuated by pharmacological inhibition of monocarboxylate transporter 2 and lactate dehydrogenase, respectively, suggesting that both cell-autonomous and non-cell-autonomous neuronal mechanisms are involved in overall lysine lactylation. In vivo , electroconvulsive stimulation increased lysine lactylation levels in the prefrontal cortices of mice, and its levels were positively correlated with the expression levels of the neuronal activity marker c-Fos on an individual cell basis. In the social defeat stress model of depression in which brain lactate levels increase, lactylation levels were increased in the prefrontal cortices of the defeated mice, which was accompanied by increased c-Fos expression, decreased social behaviors, and increased anxiety-like behaviors, suggesting that stress-induced neuronal excitation may induce lysine lactylation, thereby affecting mood-related behaviors. Further, we identified 63 candidate lysine-lactylated proteins in the mouse cortex and found that lactylation levels in histone H1 increased in response to defeat stress. This study may open up an avenue for exploration of a novel role of neuronal activity-induced lactate mediated by protein lactylation in the brain.

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  • Lactate-associated lactylation modulates glial inflammatory states and neuronal synaptic function, supporting its role in neuroplasticity.

    “Recent findings indicate that lactate-associated lactylation modulates glial inflammatory states and neuronal synaptic function, supporting its role in neuroplasticity (Yao et al., 2023; Hagihara et al., 2021).”

    From Histone modifications and depression: epigenetic mechanisms, therapeutic targets, and translational outlook (2026) · cites this paper as Hagihara et al., 2021

    In “Lactate treatment and neuronal excitation increase protein lactylation in the brain” (lines 74–92), lactate increases neuronal lactylation, and lactylation is detected in astrocytes and microglia. But the conclusion in “Identification of lactylated proteins in the brain” (lines 243–251) says its functional significance remains unclear. The paper does not establish that lactylation modulates glial inflammatory states or neuronal synaptic function, or that it has a role in neuroplasticity. (LLM, conf=0.88)

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  1. [4]4. Hagihara, H. et al. Systematic analysis of brain lactate and pH levels in 65 animal models related to neuropsychiatric conditions. bioRxiv 2021.02.02.428362 (2021).

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Authors
Hagihara, H., Shoji, H., Otabi, H., Toyoda, A., Katoh, K., Namihira, M., & Miyakawa, T.
Affiliations
  • Fujita Health University (JP)
  • Ibaraki University (JP)
  • Artificial Intelligence Research Center (JP)
  • National Institute of Advanced Industrial Science and Technology (JP)
Corresponding author
Miyakawa, Tsuyoshi
ORCID
Venue
Cell Reports
Publisher
Elsevier BV
Published
2021-10
Volume
37
Issue
2
Pages
109820
ISSN
2211-1247 (ISSN-L)
DOI
10.1016/j.celrep.2021.109820
OpenAlex
W3206354625
Cited by
349
References
66
Citations by year
2026: 63 · 2025: 102 · 2024: 78 · 2023: 71 · 2022: 32 · 2021: 3
FWCI
22.20
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Reports (publishedVersion, cc-by-nc-nd)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • SSRN Electronic Journal (acceptedVersion)
  • PubMed (publishedVersion)
Funders
  • Japan Society for the Promotion of Science (JP16H06276, JP18K07378, JP19K06502, JP20H00522)
  • Ministry of Education, Culture, Sports, Science and Technology (JP16H06462, JP17H06413, JP17H06417, JPMXP0618217663)
  • Japan Agency for Medical Research and Development (JP18dm0107101, JP20he0622012h0001)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurobiology and Insect Physiology Research
Keywords
lysine lactylation, lactate, neuronal excitation, social stress, brain cells, c-fos, anxiety-like behavior, social behavior, histone H1, post-translational modification, neuronal activity
MeSH terms
Social Defeat, Action Potentials, Animals, Anxiety, Behavior, Animal, Brain, Cells, Cultured, Histones, Lysine, Mice, Inbred C57BL, Mice, Inbred ICR, Neurons, Protein Processing, Post-Translational, Proto-Oncogene Proteins c-fos, Lactic Acid, Proteome, Mice

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