Sustained antidepressant effects of ketamine metabolite involve GABAergic inhibition-mediated molecular dynamics in aPVT glutamatergic neurons
Ayako Kawatake-Kuno, Haiyan Li, Hiromichi Inaba, Momoka Hikosaka, Erina Ishimori, Takatoshi Ueki, Y. Garkun, Hirofumi Morishita, S. Narumiya, Naoya Oishi, Gen Ohtsuki, Toshiya Murai, Shusaku Uchida
Neuron February 1, 2024 DOI: 10.1016/j.neuron.2024.01.023 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical animal study Peer reviewed |
|---|---|
| Population | Repeatedly stressed animal models |
| Interventions | (2S 6S)-hydroxynorketamine |
| Topics | Esketamine Ketamine |
| Key points | The authors report that (2S,6S)-hydroxynorketamine's sustained antidepressant-like behavioral effects in repeatedly stressed animal models involve neurobiological changes in the anterior paraventricular nucleus of the thalamus, including enhanced GABAA receptor-mediated tonic currents, nuclear export of KDM6, replacement by EZH2, increased H3K27me3 levels, and suppressed transcription of genes associated with G-protein-coupled receptor signaling. They propose these mechanisms may inform next-generation pharmacotherapies for sustained remission of stress-related psychiatric disorders. |
Abstract
Summary 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. The present study may support the development of potentially effective next-generation pharmacotherapies to promote sustained remission of stress-related psychiatric disorders.