Activity-dependent brain-derived neurotrophic factor signaling is required for the antidepressant actions of (2 R ,6 R )-hydroxynorketamine
Kenichi Fukumoto, Manoela V. Fogaça, Rong-Jian Liu, Catharine H. Duman, T. Kato, Xiaoyuan Li, Ronald S. Duman
Proceedings of the National Academy of Sciences December 17, 2018 DOI: 10.1073/pnas.1814709116 (opens in new tab) via OpenAlex
Summary
AI-generated from the abstractA metabolite of ketamine, (2R,6R)-hydroxynorketamine [(2R,6R)-HNK], produces rapid and sustained antidepressant effects in animal models without the side effects of ketamine and without blocking the NMDA receptor. The antidepressant effects require activity-dependent release of BDNF, mediated by stimulation of voltage-dependent Ca2+ channels. Increased BDNF release activates downstream TrkB and mechanistic target of rapamycin complex 1 signaling, which increases synaptic function of pyramidal neurons in the medial prefrontal cortex. Stimulation of BDNF release and increased synaptic function block or reverse the detrimental effects of stress and depression.
Study at a glance
| Characteristics | Preclinical study Peer reviewed |
|---|---|
| Population | Animal models |
| Keywords | Antidepressant Brain-derived neurotrophic factor Neurotrophic factors Neuroscience Pharmacology |
| Citations | 191 |
| Key finding | The antidepressant effects of (2R,6R)-HNK require activity-dependent release of BDNF mediated by stimulation of voltage-dependent Ca2+ channels, leading to TrkB and mTORC1 signaling that increases synaptic function in the medial prefrontal cortex. |
Abstract
Significance A metabolite of ketamine, (2 R ,6 R )-hydroxynorketamine [(2 R ,6 R )-HNK], produces rapid and sustained antidepressant effects in animal models but without the side effects of ketamine. Notably, (2 R ,6 R )-HNK does not block the NMDA receptor, the primary target of ketamine. Here, we demonstrate that the antidepressant effects of (2 R ,6 R )-HNK require activity dependent release of BDNF that is mediated by stimulation of voltage-dependent Ca 2+ channels. Importantly, increased BDNF release leads to activation of downstream TrkB and mechanistic target of rapamycin complex 1 signaling that increases synaptic function of pyramidal neurons in the medial prefrontal cortex. Stimulation of BDNF release and increased synaptic function block or reverse the detrimental effects of stress and depression and thereby underlie the antidepressant actions of (2 R ,6 R )-HNK.