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, Shusaku Uchida
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...
February 9, 2024: Neuron