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Deficiency of Glycosylated α-Dystroglycan in Ventral Hippocampus Bridges the Destabilization of Gamma-Aminobutyric Acid Type A Receptors With the Depressive-like Behaviors of Male Mice

  • Author Footnotes
    1 W-LX and H-LZ contributed equally to this work.
    Wen-Long Xie
    Footnotes
    1 W-LX and H-LZ contributed equally to this work.
    Affiliations
    Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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  • Author Footnotes
    1 W-LX and H-LZ contributed equally to this work.
    Hui-Ling Zheng
    Footnotes
    1 W-LX and H-LZ contributed equally to this work.
    Affiliations
    Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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  • Hou-Hong Li
    Affiliations
    Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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  • Jia-Jing Lu
    Affiliations
    Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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  • Shi-Ge Xue
    Affiliations
    Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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  • Yi Luo
    Affiliations
    Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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  • Cong Ma
    Affiliations
    Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
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  • Jian-Feng Liu
    Affiliations
    Sino-France Laboratory for Drug Screening, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
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  • Zhuang-Li Hu
    Affiliations
    Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Research Center for Depression, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Key Laboratory of Neurological Diseases (Huazhong University of Science and Technology), Ministry of Education of China, Wuhan, China

    Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province, Wuhan, China
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  • Lan Ni
    Affiliations
    Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province, Wuhan, China
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  • You Jin
    Affiliations
    Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province, Wuhan, China
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  • Fang Wang
    Correspondence
    Fang Wang, M.D., Ph.D.
    Affiliations
    Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Research Center for Depression, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Key Laboratory of Neurological Diseases (Huazhong University of Science and Technology), Ministry of Education of China, Wuhan, China

    Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province, Wuhan, China
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  • Jian-Guo Chen
    Correspondence
    Address correspondence to Jian-Guo Chen, M.D., Ph.D.
    Affiliations
    Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Research Center for Depression, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Key Laboratory of Neurological Diseases (Huazhong University of Science and Technology), Ministry of Education of China, Wuhan, China

    Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province, Wuhan, China
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  • Author Footnotes
    1 W-LX and H-LZ contributed equally to this work.
Published:November 09, 2021DOI:https://doi.org/10.1016/j.biopsych.2021.10.022

      Abstract

      Background

      Depression is a common psychiatric disorder associated with defects in GABAergic (gamma-aminobutyric acidergic) neurotransmission. α-Dystroglycan (α-DG), a cell adhesion molecule known to be essential for skeletal muscle integrity, is also present at inhibitory synapses in the central nervous system and forms a structural element in certain synapses. However, the role of α-DG in the regulation of depressive-like behaviors remains largely unknown.

      Methods

      Depressive-like behaviors were induced by chronic social defeat stress in adult male mice. Surface protein was extracted by a biotin kit, and the expression of protein was detected by Western blotting. Intrahippocampal microinjection of the lentivirus or adeno-associated virus or agrin intervention was carried out using a stereotaxic instrument and followed by behavioral tests. Miniature inhibitory postsynaptic currents were recorded by whole-cell patch-clamp techniques.

      Results

      The expression of α-DG and glycosylated α-DG in the ventral hippocampus was significantly lower in chronic social defeat stress–susceptible male mice than in control mice, accompanied by a decreased surface expression of GABAA receptor γ2 subunit and reduced GABAergic neurotransmission. RNA interference–mediated knockdown of Dag1 increased the susceptibility of mice to subthreshold stress. Both in vivo administration of agrin and overexpression of like-acetylglucosaminyltransferase ameliorated depressive-like behaviors and restored the decrease in surface expression of GABAA receptor γ2 subunit and the amplitude of miniature inhibitory postsynaptic currents in chronic social defeat stress–exposed mice.

      Conclusions

      Our findings demonstrate that glycosylated α-DG plays a role in the pathophysiological process of depressive-like behaviors by regulating the surface expression of GABAA receptor γ2 subunit and GABAergic neurotransmission in the ventral hippocampus.

      Keywords

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