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Enhanced TARP-γ8-PSD-95 coupling in excitatory neurons contributes to the rapid antidepressant-like action of ketamine in male mice

Author

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  • Shi-Ge Xue

    (Huazhong University of Science and Technology)

  • Jin-Gang He

    (Huazhong University of Science and Technology
    The Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province
    Tongji Medical College, Huazhong University of Science
    Key Laboratory of Neurological Diseases (HUST), Ministry of Education of China)

  • Ling-Li Lu

    (Huazhong University of Science and Technology)

  • Shi-Jie Song

    (Huazhong University of Science and Technology)

  • Mei-Mei Chen

    (Huazhong University of Science and Technology)

  • Fang Wang

    (Huazhong University of Science and Technology
    The Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province
    Tongji Medical College, Huazhong University of Science
    Key Laboratory of Neurological Diseases (HUST), Ministry of Education of China)

  • Jian-Guo Chen

    (Huazhong University of Science and Technology
    The Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province
    Tongji Medical College, Huazhong University of Science
    Key Laboratory of Neurological Diseases (HUST), Ministry of Education of China)

Abstract

Ketamine produces rapid antidepressant effects at sub-anesthetic dosage through early and sustained activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs), however, the exact molecular mechanism still remains unclear. Transmembrane AMPAR regulatory protein-γ8 (TARP-γ8) is identified as one of AMPAR auxiliary subunits, which controls assemblies, surface trafficking and gating of AMPARs. Here, we show that ketamine rescues both depressive-like behaviors and the decreased AMPARs-mediated neurotransmission by recruitment of TARP-γ8 at the postsynaptic sites in the ventral hippocampus of stressed male mice. Furthermore, the rapid antidepressant effects of ketamine are abolished by selective blockade of TARP-γ8-containing AMPAR or uncoupling of TARP-γ8 from PSD-95. Overexpression of TARP-γ8 reverses chronic stress-induced depressive-like behaviors and attenuation of AMPARs-mediated neurotransmission. Conversely, knockdown of TARP-γ8 in excitatory neurons prevents the rapid antidepressant effects of ketamine.

Suggested Citation

  • Shi-Ge Xue & Jin-Gang He & Ling-Li Lu & Shi-Jie Song & Mei-Mei Chen & Fang Wang & Jian-Guo Chen, 2023. "Enhanced TARP-γ8-PSD-95 coupling in excitatory neurons contributes to the rapid antidepressant-like action of ketamine in male mice," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-42780-8
    DOI: 10.1038/s41467-023-42780-8
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    References listed on IDEAS

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    1. Panos Zanos & Ruin Moaddel & Patrick J. Morris & Polymnia Georgiou & Jonathan Fischell & Greg I. Elmer & Manickavasagom Alkondon & Peixiong Yuan & Heather J. Pribut & Nagendra S. Singh & Katina S. S. , 2016. "NMDAR inhibition-independent antidepressant actions of ketamine metabolites," Nature, Nature, vol. 533(7604), pages 481-486, May.
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