Ketamine exhibits superior efficacy compared to conventional antidepressants, yet its clinical application remains limited by dose-dependent side effects. Ascorbic acid (AA) augments ketamine's antidepressant-like effects, suggesting that AA co-administration with subtherapeutic ketamine doses may achieve optimal efficacy while improving safety. Since AA itself lacks independently clinical antidepressant efficacy, its enhancement on the efficacy of ketamine raises a mechanistic question. This study investigated the antidepressant-like effects of AA combined with esketamine (ketamine's S-enantiomer) and elucidated the role of hippocampal TARP-γ8-containing AMPA receptors (AMPARs) in this enhancement. We employed a chronic restraint stress-induced mouse model of depression to evaluate depressive-like behaviors, hippocampal synaptic markers, and neural plasticity. The effects of AA, esketamine, and their combination were examined, along with pharmacological modulation of hippocampal TARP-γ8-containing AMPARs. Our findings demonstrated that AA enhanced the action of a subeffective dose of esketamine, fully reversing both behavioral and synaptic deficits in depressed mice to levels comparable with healthy controls. This combinatorial effect was equivalent to that achieved by an effective dose of esketamine alone. Selective pharmacological blockade of hippocampal TARP-γ8-containing AMPARs completely abolished the antidepressant-like efficacy of the subeffective-dosed AA-esketamine combination. However, the same blockade did not affect baseline depressive-like phenotypes in depressed mice or the inactivity of either agent at subeffective dose alone. These results indicate that AA's enhancement of esketamine's antidepressant-like effects requires the dependent mediation of hippocampal TARP-γ8-containing AMPARs for synaptic modulation, providing both mechanistic insight and potential clinical implications for optimizing ketamine-based strategies of therapeutics for depression.
