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Altered Calcium Permeability of AMPA Receptor Drives NMDA Receptor Inhibition in the Hippocampus of Murine Obesity Models

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Abstract

Evidence has accumulated that higher consumption of high-fat diets (HFDs) during the juvenile/adolescent period induces altered hippocampal function and morphology; however, the mechanism behind this phenomenon remains elusive. Using high-resolution structural imaging combined with molecular and functional interrogation, a murine model of obesity treated with HFDs for 12 weeks after weaning mice was shown to change in the glutamate-mediated intracellular calcium signaling and activity, including further selective reduction of gray matter volume in the hippocampus associated with memory recall disturbance. Dysregulation of intracellular calcium concentrations was restored by a non-competitive α-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) antagonist, followed by normalization of hippocampal volume and memory recall ability, indicating that AMPARs may serve as an attractive therapeutic target for obesity-associated cognitive decline.

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Data Availability

The datasets that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

The authors wish to acknowledge Professor Kenzo Takahashi (University of the Ryukyus) for his critical review of our manuscript. The authors wish to acknowledge Professor Yamamoto, Chief Executive Officer of OIST’s MRI system. Rodent MRI was performed at the University of the Ryukyus under the OIST Sign Cooperation Agreement. The authors wish to acknowledge Mr. Yasuhiko Sato and Mr. Masato Takiguchi (Carl Zeiss) for their special technical support and Mr. Yoshiki Ohshiro for his secretarial assistance.

Funding

This work was supported by Grants-in-Aid for Scientific Research (B) (23390352) (to S.I.); Grants-in-Aid for Scientific Research (A) (17H01403) (to S.I.); Challenging Exploratory Research (24650168) (to S.I.) by the Ministry of Education, Culture, Sports, Science and Technology in Japan; the Industrial Disease Clinical Research Grants by the Ministry of Health, Labor, and Welfare (14050101–01) (to S.I.); Special Account Budget for Education and Research (2011–2013, 2011–2015, 2014–2018, 2015–2019) (to S.I.); Grants for the Princess Takamatsu Cancer Fund (to S.I.); and the Grants for Takeda Science Foundation (to S.I.).

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Authors and Affiliations

  1. Department of Neurosurgery, Graduate School of Medicine, University of the Ryukyus, 207 Uehara, Nishihara-machi, Okinawa, 903-0215, Japan

    Yasuyo Miyagi, Kyoko Fujiwara, Chiaki Katagiri, Masahiko Nishimura, Hiroshi Takagi & Shogo Ishiuchi

  2. Animal Resources Section, Okinawa Institute of Science and Technology Graduate University, 1919-1 Tancha, Onna-son, Kunigami, Okinawa, 904-0495, Japan

    Keigo Hikishima

  3. Department of Dermatology, and Advanced Medical Research Center, Graduate School of Medicine, University of the Ryukyus, 207 Uehara, Nishihara-machi, Okinawa, 903-0215, Japan

    Daisuke Utsumi

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  1. Yasuyo Miyagi
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Contributions

YM contributed qRT-PCR, Q/R, rodent behavioral analysis, and planning of animal experimental design. KF contributed Immunohistochemical analysis. KH contributed Rodent MRI imaging. DU contributed NGS analysis. CK contributed Western blot analysis. MN contributed Human and rodent MRI imaging and network analysis. HT contributed Ca2+ imaging and editing of the manuscript. SI contributed Z1 imaging, Golgi staining, project administration, funding acquisition, conceptualization and writing, and review and editing of the manuscript.

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Correspondence to Shogo Ishiuchi.

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All animal experiments were performed in accordance with the guidelines of the Animal Experiment Ethics Committee of the University of the Ryukyus (approval number: A2019239). All experiments were approved by the ethical committee of the University of the Ryukyus for medical and health research involving human subjects and were performed in accordance with guidelines of human experiment regulations at University of the Ryukyus (approval number: 111).

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Miyagi, Y., Fujiwara, K., Hikishima, K. et al. Altered Calcium Permeability of AMPA Receptor Drives NMDA Receptor Inhibition in the Hippocampus of Murine Obesity Models. Mol Neurobiol 59, 4902–4925 (2022). https://doi.org/10.1007/s12035-022-02834-2

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