Novel contribution of cell surface and intracellular M1-muscarinic acetylcholine receptors to synaptic plasticity in hippocampus

Authors

  • Abu Syed Md Anisuzzaman,

    1. Division of Pharmacology, Department of Biochemistry and Bioinformative Sciences, School of Medicine, University of Fukui, Eiheiji, Japan
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    • These authors contributed equally to this study.
  • Junsuke Uwada,

    1. Division of Pharmacology, Department of Biochemistry and Bioinformative Sciences, School of Medicine, University of Fukui, Eiheiji, Japan
    2. Organization for Life Science Advancement Programs, University of Fukui, Eiheiji, Japan
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    • These authors contributed equally to this study.
  • Takayoshi Masuoka,

    1. Department of Pharmacology, School of Medicine, Kanazawa Medical University, Uchinada, Japan
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    • These authors contributed equally to this study.
  • Hatsumi Yoshiki,

    1. Division of Pharmacology, Department of Biochemistry and Bioinformative Sciences, School of Medicine, University of Fukui, Eiheiji, Japan
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  • Matomo Nishio,

    1. Department of Pharmacology, School of Medicine, Kanazawa Medical University, Uchinada, Japan
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  • Yuji Ikegaya,

    1. Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo Bunkyo-ku, Japan
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  • Naoya Takahashi,

    1. Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo Bunkyo-ku, Japan
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  • Norio Matsuki,

    1. Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo Bunkyo-ku, Japan
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  • Yasuhisa Fujibayashi,

    1. Biomedical Imaging Research Center, University of Fukui, Eiheiji, Japan
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  • Yoshiharu Yonekura,

    1. Biomedical Imaging Research Center, University of Fukui, Eiheiji, Japan
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  • Toshihiko Momiyama,

    1. Department of Pharmacology, Jikei University School of Medicine, Minato-ku, Japan
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  • Ikunobu Muramatsu

    Corresponding author
    1. Organization for Life Science Advancement Programs, University of Fukui, Eiheiji, Japan
    2. Child Development Research Center, Graduate School of Medicine, University of Fukui, Eiheiji, Japan
    • Division of Pharmacology, Department of Biochemistry and Bioinformative Sciences, School of Medicine, University of Fukui, Eiheiji, Japan
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Address correspondence and reprint requests to Ikunobu Muramatsu, Division of Pharmacology, Department of Biochemistry and Bioinformative Sciences, School of Medicine, University of Fukui, Eiheiji, Fukui 910-1193, Japan. E-mail: muramatu@u-fukui.ac.jp

Abstract

Muscarinic acetylcholine receptors (mAChRs) are well known to transmit extracellular cholinergic signals into the cytoplasm from their position on the cell surface. However, we show here that M1-mAChRs are also highly expressed on intracellular membranes in neurons of the telencephalon and activate signaling cascades distinct from those of cell surface receptors, contributing uniquely to synaptic plasticity. Radioligand-binding experiments with cell-permeable and -impermeable ligands and immunohistochemical observations revealed intracellular and surface distributions of M1-mAChRs in the hippocampus and cortex of rats, mice, and humans, in contrast to the selective occurrence on the cell surface in other tissues. All intracellular muscarinic-binding sites were abolished in M1-mAChR-gene-knockout mice. Activation of cell surface M1-mAChRs in rat hippocampal neurons evoked phosphatidylinositol hydrolysis and network oscillations at theta rhythm, and transiently enhanced long-term potentiation. On the other hand, activation of intracellular M1-mAChRs phosphorylated extracellular-regulated kinase 1/2 and gradually enhanced long-term potentiation. Our data thus demonstrate that M1-mAChRs function at both surface and intracellular sites in telencephalon neurons including the hippocampus, suggesting a new mode of cholinergic transmission in the central nervous system.

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