A synaptic locus for TrkB signaling underlying ketamine rapid antidepressant action

• Published in: Cell reports (Cambridge) 2021-08, Vol.36 (7), p.109513-109513, Article 109513
• Main Authors: Lin, Pei-Yi, Ma, Z. Zack, Mahgoub, Melissa, Kavalali, Ege T., Monteggia, Lisa M.
• Format: Article
• Language: English
• Subjects: Animals; antidepressant; Antidepressive Agents - pharmacology; BDNF; Brain-Derived Neurotrophic Factor - metabolism; CA1 Region, Hippocampal - drug effects; CA1 Region, Hippocampal - metabolism; CA3 Region, Hippocampal - drug effects; CA3 Region, Hippocampal - metabolism; CA3-CA1 synapse; dynamin1; Dynamins - metabolism; Endocytosis - drug effects; HEK293 Cells; hippocampus; Humans; ketamine; Ketamine - pharmacology; Mice; Neurons - metabolism; Receptor, trkB - metabolism; Schaffer collateral; Signal Transduction - drug effects; Synapses - drug effects; Synapses - metabolism; synaptic potentiation; TrkB
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2021.109513

Ketamine produces rapid antidepressant action in patients with major depression or treatment-resistant depression. Studies have identified brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin receptor kinase B (TrkB), as necessary for the antidepressant effects and underlying ketamine-induced synaptic potentiation in the hippocampus. Here, we delete BDNF or TrkB in presynaptic CA3 or postsynaptic CA1 regions of the Schaffer collateral pathway to investigate the rapid antidepressant action of ketamine. The deletion of Bdnf in CA3 or CA1 blocks the ketamine-induced synaptic potentiation. In contrast, ablation of TrkB only in postsynaptic CA1 eliminates the ketamine-induced synaptic potentiation. We confirm BDNF-TrkB signaling in CA1 is required for ketamine’s rapid behavioral action. Moreover, ketamine application elicits dynamin1-dependent TrkB activation and downstream signaling to trigger rapid synaptic effects. Taken together, these data demonstrate a requirement for BDNF-TrkB signaling in CA1 neurons in ketamine-induced synaptic potentiation and identify a specific synaptic locus in eliciting ketamine’s rapid antidepressant effects. [Display omitted] •BDNF-TrkB signaling at CA3-CA1 synapses is essential for ketamine’s action•Ketamine induces synaptic potentiation that depends on TrkB in CA1•Ketamine elicits dynamin-1-dependent TrkB activation and downstream signaling Lin et al. report the essential role of BDNF signaling through postsynaptic TrkB at CA3-CA1 synapses in ketamine’s synaptic potentiation and rapid antidepressant action. These findings establish a strong correlation between TrkB-dependent potentiation at the CA1 synaptic locus and the antidepressant behavioral action of ketamine.