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Astrocytes Render Memory Flexible by Releasing D-Serine and Regulating NMDA Receptor Tone in the Hippocampus

  • Wuhyun Koh
    Affiliations
    Center for Cognition and Sociality, Institute for Basic Science, Daejeon, South Korea

    Department of Neuroscience, Division of BioMedical Science & Technology, Korea Institute of Science and Technology School, Korea University of Science and Technology, Seoul, South Korea

    Center for Functional Connectomics, Brain Science Institute, Korea Institute of Science and Technology, Seoul, South Korea
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  • Mijeong Park
    Affiliations
    Department of Neuroscience, Division of BioMedical Science & Technology, Korea Institute of Science and Technology School, Korea University of Science and Technology, Seoul, South Korea

    Center for Neuroscience, Brain Science Institute, Korea Institute of Science and Technology, Seoul, South Korea
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  • Ye Eun Chun
    Affiliations
    Department of Neuroscience, Division of BioMedical Science & Technology, Korea Institute of Science and Technology School, Korea University of Science and Technology, Seoul, South Korea

    Center for Functional Connectomics, Brain Science Institute, Korea Institute of Science and Technology, Seoul, South Korea
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  • Jaekwang Lee
    Affiliations
    Center for Functional Connectomics, Brain Science Institute, Korea Institute of Science and Technology, Seoul, South Korea
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  • Hyun Soo Shim
    Affiliations
    Center for Neuroscience, Brain Science Institute, Korea Institute of Science and Technology, Seoul, South Korea
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  • Mingu Gordon Park
    Affiliations
    Center for Cognition and Sociality, Institute for Basic Science, Daejeon, South Korea

    KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, South Korea
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  • Sunpil Kim
    Affiliations
    Center for Cognition and Sociality, Institute for Basic Science, Daejeon, South Korea

    KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, South Korea

    Center for Functional Connectomics, Brain Science Institute, Korea Institute of Science and Technology, Seoul, South Korea
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  • Moonsun Sa
    Affiliations
    Center for Cognition and Sociality, Institute for Basic Science, Daejeon, South Korea

    KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, South Korea
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  • Jinhyeong Joo
    Affiliations
    Center for Cognition and Sociality, Institute for Basic Science, Daejeon, South Korea

    IBS School, Korea University of Science and Technology, Daejeon, South Korea
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  • Hyunji Kang
    Affiliations
    Center for Cognition and Sociality, Institute for Basic Science, Daejeon, South Korea

    IBS School, Korea University of Science and Technology, Daejeon, South Korea
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  • Soo-Jin Oh
    Affiliations
    Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology, Seoul, South Korea

    Center for Neuroscience, Brain Science Institute, Korea Institute of Science and Technology, Seoul, South Korea
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  • Junsung Woo
    Affiliations
    Department of Neuroscience, Division of BioMedical Science & Technology, Korea Institute of Science and Technology School, Korea University of Science and Technology, Seoul, South Korea

    Center for Functional Connectomics, Brain Science Institute, Korea Institute of Science and Technology, Seoul, South Korea
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  • Heejung Chun
    Affiliations
    Center for Cognition and Sociality, Institute for Basic Science, Daejeon, South Korea

    Center for Functional Connectomics, Brain Science Institute, Korea Institute of Science and Technology, Seoul, South Korea
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  • Seung Eun Lee
    Affiliations
    Virus Facility, Research Animal Resource Center, Korea Institute of Science and Technology, Seoul, South Korea
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  • Jinpyo Hong
    Affiliations
    Center for Functional Connectomics, Brain Science Institute, Korea Institute of Science and Technology, Seoul, South Korea
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  • Jiesi Feng
    Affiliations
    State Key Laboratory of Membrane Biology, Peking University School of Life Sciences, Beijing, China
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  • Yulong Li
    Affiliations
    State Key Laboratory of Membrane Biology, Peking University School of Life Sciences, Beijing, China
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  • Hoon Ryu
    Affiliations
    Center for Neuroscience, Brain Science Institute, Korea Institute of Science and Technology, Seoul, South Korea
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  • Jeiwon Cho
    Affiliations
    Brain and Cognitive Science, Scranton College, Ewha Womans University, Seoul, South Korea
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  • C. Justin Lee
    Correspondence
    Address correspondence to C. Justin Lee, Ph.D.
    Affiliations
    Department of Neuroscience, Division of BioMedical Science & Technology, Korea Institute of Science and Technology School, Korea University of Science and Technology, Seoul, South Korea

    KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, South Korea

    KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, South Korea

    IBS School, Korea University of Science and Technology, Daejeon, South Korea
    Search for articles by this author

      Abstract

      Background

      NMDA receptor (NMDAR) hypofunction has been implicated in several psychiatric disorders with impairment of cognitive flexibility. However, the molecular mechanism of how NMDAR hypofunction with decreased NMDAR tone causes the impairment of cognitive flexibility has been minimally understood. Furthermore, it has been unclear whether hippocampal astrocytes regulate NMDAR tone and cognitive flexibility.

      Methods

      We employed cell type–specific genetic manipulations, ex vivo electrophysiological recordings, sniffer patch recordings, cutting-edge biosensor for norepinephrine, and behavioral assays to investigate whether astrocytes can regulate NMDAR tone by releasing D-serine and glutamate. Subsequently, we further investigated the role of NMDAR tone in heterosynaptic long-term depression, metaplasticity, and cognitive flexibility.

      Results

      We found that hippocampal astrocytes regulate NMDAR tone via BEST1-mediated corelease of D-serine and glutamate. Best1 knockout mice exhibited reduced NMDAR tone and impairments of homosynaptic and α1 adrenergic receptor–dependent heterosynaptic long-term depression, which leads to defects in metaplasticity and cognitive flexibility. These impairments in Best1 knockout mice can be rescued by hippocampal astrocyte-specific BEST1 expression or enhanced NMDAR tone through D-serine supplement. D-serine injection in Best1 knockout mice during initial learning rescues subsequent reversal learning.

      Conclusions

      These findings indicate that NMDAR tone during initial learning is important for subsequent learning, and hippocampal NMDAR tone regulated by astrocytic BEST1 is critical for heterosynaptic long-term depression, metaplasticity, and cognitive flexibility.

      Keywords

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