Sustained antidepressant effects of ketamine metabolite involve GABAergic inhibition-mediated molecular dynamics in aPVT glutamatergic neurons

Despite the rapid and sustained antidepressant effects of ketamine and its metabolites, their underlying cellular and molecular mechanisms are not fully understood. Here, we demonstrate that the sustained antidepressant-like behavioral effects of (2S,6S)-hydroxynorketamine (HNK) in repeatedly stressed animal models involve neurobiological changes in the anterior paraventricular nucleus of the thalamus (aPVT). Mechanistically, (2S,6S)-HNK induces mRNA expression of extrasynaptic GABAA receptors and subsequently enhances GABAA-receptor-mediated tonic currents, leading to the nuclear export of histone demethylase KDM6 and its replacement by histone methyltransferase EZH2. This process increases H3K27me3 levels, which in turn suppresses the transcription of genes associated with G-protein-coupled receptor signaling. Thus, our findings shed light on the comprehensive cellular and molecular mechanisms in aPVT underlying the sustained antidepressant behavioral effects of ketamine metabolites. This study may support the development of potentially effective next-generation pharmacotherapies to promote sustained remission of stress-related psychiatric disorders. •aPVT is crucial for (2S,6S)-HNK’s sustained antidepressant-like effects•(2S,6S)-HNK increases the expression of GABAARs and tonic GABAergic currents•Substituting KDM6 by EZH2 represses Gnb3, inducing the antidepressant effects•KDM6 and EZH2 are involved in (2S,6S)-HNK’s sustained antidepressant effects Kawatake-Kuno, Li, Inaba, et al. considered a midline thalamic structure, the aPVT, a crucial brain region involved in the sustained antidepressant-like effects of the ketamine metabolite (2S,6S)-HNK. Moreover, they uncover the mechanisms whereby this drug drives its antidepressant-like effects via modulation of GABAergic-inhibition-mediated epigenetic regulations in the aPVT.