A synaptic locus for TrkB signaling underlying ketamine rapid antidepressant action
Pei-Yi Lin, Z. Z. Ma, Melissa Mahgoub, E. Kavalali, L. Monteggia
Cell Reports August 1, 2021 DOI: 10.1016/j.celrep.2021.109513 via Semantic Scholar
Summary
Ketamine rapidly relieves depression by activating BDNF-TrkB signaling specifically in CA1 neurons of the hippocampus. Deleting BDNF in either CA3 or CA1, or deleting its receptor TrkB only in postsynaptic CA1, blocks ketamine-induced synaptic strengthening. Ketamine triggers dynamin1-dependent TrkB activation and downstream signaling to produce these rapid synaptic effects. The findings pinpoint a precise synaptic location—CA1 neurons—where BDNF-TrkB signaling is required for ketamine's rapid antidepressant action.
Study at a glance
| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Mice with targeted gene deletions in hippocampal CA3 or CA1 regions |
| Keywords | Medicine Biology |
| Citations | 97 |
| Key finding | BDNF-TrkB signaling in postsynaptic CA1 neurons is required for ketamine-induced synaptic potentiation and rapid antidepressant effects. |
Abstract
SUMMARY 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.