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

Shi-Ge Xue, Jin-Gang He, Ling-Li Lu, Shi-Jie Song, Mei-Mei Chen, Fang Wang () and Jian-Guo Chen ()
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Shi-Ge Xue: Huazhong University of Science and Technology
Jin-Gang He: Huazhong University of Science and Technology
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
Jian-Guo Chen: Huazhong University of Science and Technology

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-42780-8

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