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JADE2 Is Essential for Hippocampal Synaptic Plasticity and Cognitive Functions in Mice

  • Author Footnotes
    1 MF and YL contributed equally to this work.
    Minghua Fan
    Footnotes
    1 MF and YL contributed equally to this work.
    Affiliations
    State Key Laboratory of Natural and Biomimetic Drugs, Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing, China
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  • Author Footnotes
    1 MF and YL contributed equally to this work.
    Yongqing Liu
    Correspondence
    Yongqing Liu, Ph.D.
    Footnotes
    1 MF and YL contributed equally to this work.
    Affiliations
    State Key Laboratory of Natural and Biomimetic Drugs, Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing, China
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  • Yongfeng Shang
    Affiliations
    Department of Biochemistry and Biophysics, School of Basic Medical Sciences, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Health Science Center, Beijing, China

    Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Hangzhou Normal University, Hangzhou, China
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  • Yanxue Xue
    Affiliations
    National Institute on Drug Dependence and Beijing Key Laboratory of Drug Dependence, Peking University, Beijing, China

    Chinese Institute for Brain Research, Beijing, China
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  • Jing Liang
    Affiliations
    Department of Biochemistry and Biophysics, School of Basic Medical Sciences, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Health Science Center, Beijing, China
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  • Zhuo Huang
    Correspondence
    Address correspondence to Zhuo Huang, Ph.D.
    Affiliations
    State Key Laboratory of Natural and Biomimetic Drugs, Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing, China

    IDG/McGovern Institute for Brain Research, Peking University, Beijing, China
    Search for articles by this author
  • Author Footnotes
    1 MF and YL contributed equally to this work.

      Abstract

      Background

      Impairment of synaptic plasticity is closely correlated with a range of pathological conditions, such as cognitive deficits. However, how synaptic efficacy is regulated remains incompletely understood. Here, we report that the epigenetic factor JADE2 was indispensable for the maintenance of hippocampal synaptic plasticity and cognitive functions in mice.

      Methods

      We used the Morris water maze and the fear conditioning test to examine learning-related behaviors. In addition, Western blotting, viral-mediated JADE2 manipulations, RNA sequencing, and electrophysiological recordings were used to address our questions.

      Results

      JADE2 expression is increased upon enhanced neuronal activity in vitro and in vivo. Knockdown or genetic deletion of Jade2 in hippocampal CA1 results in impaired structural and functional synaptic plasticity, leading to memory impairment, whereas overexpression of JADE2 in CA1 neurons facilitates hippocampal-dependent learning and memory. Mechanistically, our data show that JADE2 modulates synaptic functions mainly by transcriptional activation of cytoskeletal regulator Rac1, and this activity is dependent on its interaction with histone acetyltransferase HBO1. Finally, we demonstrate that restoring RAC1 expression in Jade2 knockout mice could rescue the deficits in synaptic plasticity and learning-related behaviors.

      Conclusions

      Our findings reveal that JADE2 plays a critical role in regulating synaptic plasticity and memory formation, suggesting that activity-dependent epigenetic regulation is an important molecular mechanism in controlling synaptic plasticity.

      Keywords

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