谷氨酸的
加巴能
神经科学
氯胺酮
抗抑郁药
代谢物
动力学(音乐)
谷氨酸受体
药理学
心理学
生物
海马体
医学
内科学
抑制性突触后电位
内分泌学
受体
教育学
作者
Ayako Kawatake-Kuno,Haiyan Li,Hiromichi Inaba,Momoka Hikosaka,Erina Ishimori,Takatoshi Ueki,Yury Garkun,Hirofumi Morishita,Shuh Narumiya,Naoya Oishi,Gen Ohtsuki,Toshiya Murai,Shinichi Uchida
出处
期刊:Neuron
[Elsevier]
日期:2024-02-01
标识
DOI:10.1016/j.neuron.2024.01.023
摘要
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. This study may support the development of potentially effective next-generation pharmacotherapies to promote sustained remission of stress-related psychiatric disorders.
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