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

• Published in: Nature communications Vol. 14; no. 1; p. 7971
• Main Authors: Xue, Shi-Ge, He, Jin-Gang, Lu, Ling-Li, Song, Shi-Jie, Chen, Mei-Mei, Wang, Fang, Chen, Jian-Guo
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group 02.12.2023; Nature Publishing Group UK; Nature Portfolio
• Subjects: Antidepressants; Channel gating; Glutamatergic transmission; Hippocampus; Ketamine; Males; Molecular modelling; Neurons; Neurotransmission; Postsynaptic density proteins; α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-42780-8

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.