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Chronic Hyponatremia Potentiates Innate Anxiety-Like Behaviors Through the Dysfunction of Monoaminergic Neurons in Mice

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Abstract

Hyponatremia is the most common clinical electrolyte disorder. Once thought to be asymptomatic in response to adaptation by the brain, recent evidence suggests that chronic hyponatremia (CHN) may induce neurological manifestations, including psychological symptoms. However, the specific psychological symptoms induced by CHN, the mechanisms underlying these symptoms, and their potential reversibility remain unclear. Therefore, this study aimed to determine whether monoaminergic neurotransmission is associated with innate anxiety-like behaviors potentiated by CHN in a mouse model of CHN secondary to the syndrome of inappropriate antidiuresis. In the present study, using a mouse model of the syndrome of inappropriate antidiuresis presenting with CHN, we showed that the sustained reduction of serum sodium ion concentrations potentiated innate anxiety-like behaviors in the light/dark transition and open field tests. We also found that serotonin and dopamine levels in the amygdala were significantly lower in mice with CHN than in controls. Additionally, phosphorylation of extracellular signal-regulated kinase (ERK) in the amygdala was significantly reduced in mice with CHN. Notably, after correcting for CHN, the increased innate anxiety-like behaviors, decreased serotonin and dopamine levels, and reduced phosphorylation of ERK in the amygdala were normalized. These findings further underscore the importance of treating CHN and highlight potential therapeutic strategies for alleviating anxiety in patients with CHN, which will improve their quality of life.

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The data underlying this article will be shared on reasonable request to the corresponding author.

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Acknowledgements

We sincerely thank Asami Yamaguchi for technical assistance.

Funding

This work was supported by JSPS KAKENHI (Grant Number 20 K08919 to Yoshihisa Sugimura, 22 K16229 to Haruki Fujisawa), The Salt Science Research Foundation No. 22 C2, YOKOYAMA Foundation for Clinical Pharmacology, The Hori Science And Arts Foundation, The Nitto Foundation, and MEXT Promotion of Distinctive Joint Research Center Program (Grant Number FY2018-2020 JPMXP0618217663, FY2021-2023 JPMXP0621467949).

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Author notes

  1. Haruki Fujisawa and Nobuhiko Magara contributed equally to this work.

Authors and Affiliations

  1. Department of Endocrinology, Diabetes and Metabolism, School of Medicine, Fujita Health University, 1-98 Dengakugakubo, Kutsukake-Cho, Toyoake, Aichi, 470-1192, Japan

    Haruki Fujisawa, Nobuhiko Magara, Shogo Nakayama, Sachiho Fuse, Naoko Iwata, Yusuke Seino, Atsushi Suzuki & Yoshihisa Sugimura

  2. Department of Endocrinology and Diabetes, Daido Hospital, Nagoya, Aichi, 457-8511, Japan

    Naoko Iwata

  3. Department of Regulatory Science for Evaluation & Development of Pharmaceuticals & Devices, Fujita Health University Graduate School of Medical Science, Toyoake, Aichi, 470-1192, Japan

    Masaya Hasegawa, Hisayoshi Kubota & Akihiro Mouri

  4. Division of Systems Medical Science, Center for Medical Science, Fujita Health University, Toyoake, Aichi, 470‑1192, Japan

    Hirotaka Shoji, Satoko Hattori, Hideo Hagihara & Tsuyoshi Miyakawa

  5. Research Creation Support Center, Aichi Medical University, Nagakute, Aichi, 480-1195, Japan

    Satoko Hattori

  6. Department of Advanced Diagnostic System Development, Fujita Health University Graduate School of Medical Sciences, Toyoake, Aichi, 470-1192, Japan

    Hidetsugu Fujigaki

  7. Laboratory of Health and Medical Science Innovation (HMSI), Fujita Health University Graduate School of Medical Science, Toyoake, Aichi, 470-1192, Japan

    Toshitaka Nabeshima

Authors
  1. Haruki Fujisawa
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  2. Nobuhiko Magara
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  17. Yoshihisa Sugimura
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Contributions

Haruki Fujisawa; Conceptualization, Formal analysis, Funding acquisition, Investigation, Validation, Visualization, Project administration, Writing – original draft. Nobuhiko Magara: Investigation. Shogo Nakayama: Investigation. Sachiho Fuse: Investigation. Naoko Iwata: Formal analysis, Validation. Masaya Hasegawa: Investigation, Formal analysis. Hisayoshi Kubota: Investigation, Formal analysis, Writing – review & editing. Hirotaka Shoji: Methodology, Software, Writing – review & editing. Satoko Hattori: Formal analysis, Methodology, Software, Validation, Writing – review & editing. Hideo Hagihara: Methodology, Software, Writing – review & editing. Hidetsugu Fujigaki: Investigation, Methodology, Writing – review & editing. Yusuke Seino: Writing – review & editing. Akihiro Mouri: Investigation, Supervision, Writing – review & editing. Tsuyoshi Miyakawa: Funding acquisition, Supervision, Writing – review & editing. Toshitaka Nabeshima: Supervision, Writing – review & editing. Suzuki Atsushi: Supervision, Writing – review & editing. Yoshihisa Sugimura: Conceptualization, Funding acquisition, Project administration, Supervision, Writing – review & editing.

Corresponding authors

Correspondence to Haruki Fujisawa or Yoshihisa Sugimura.

Ethics declarations

Ethics Approval

All procedures were performed in accordance with the institutional guidelines for animal care at Fujita Health University, Japan, which conformed to the National Institutes of Health Animal Care Guidelines and were approved by the Institutional Animal Care and Use Committee of Fujita Health University (approval number APU22094).

Consent to Participate

Not applicable.

Consent for Publication

All authors have approved the final manuscript for publication.

Conflict of interest

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Fujisawa, H., Magara, N., Nakayama, S. et al. Chronic Hyponatremia Potentiates Innate Anxiety-Like Behaviors Through the Dysfunction of Monoaminergic Neurons in Mice. Mol Neurobiol (2025). https://doi.org/10.1007/s12035-025-05024-y

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