Enhanced TARP-γ8-PSD-95 coupling in excitatory neurons contributes to the rapid antidepressant-like action of ketamine in male mice
Nature Communications December 2, 2023 Shi-Ge Xue, Jin-Gang He, Ling-Li Lu et al.
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.