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

Ketamine's rapid antidepressant effects rely on the recruitment of TARP-γ8, a protein that regulates AMPA receptors, to postsynaptic sites in the ventral hippocampus of stressed male mice. Blocking TARP-γ8-containing AMPA receptors or uncoupling TARP-γ8 from PSD-95 abolished ketamine's rapid antidepressant effects. Overexpression of TARP-γ8 reversed chronic stress-induced depressive-like behaviors and reduced AMPA receptor-mediated neurotransmission, while knockdown of TARP-γ8 in excitatory neurons prevented ketamine's rapid effects. The findings suggest TARP-γ8 is a key molecular target for ketamine's antidepressant action.

Study at a glance

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.