From Rapid Synaptic Events to Lasting Antidepressant States: Convergent and Divergent Mechanisms of Ketamine and Psychedelics

Rapid-acting antidepressants have challenged the long-standing view that therapeutic improvement in major depressive disorder requires chronic treatment with monoaminergic agents. Ketamine and classical psychedelics act through distinct proximal targets, yet both can produce rapid and persistent behavioral effects that implicate synaptic and circuit plasticity as the core mechanisms of antidepressant action. This review, based on a minisymposium presented at the 2026 Society for Neuroscience meeting, examines how brief pharmacological perturbations translate into lasting changes in mood-related networks. We first discuss hippocampal mechanisms underlying ketamine action, which include brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB)-dependent homeostatic potentiation, TrkB cross talk with metabotropic glutamate receptor 5 (mGluR5) at CA3→CA1 synapses, extracellular signal-regulated kinase (ERK)-dual-specificity phosphatase 6 (DUSP6)-mediated extension of synaptic metaplasticity, and BDNF release at mossy fiber synapses and dentate gyrus neuronal maturation. We then consider how these local plasticity mechanisms interface with distributed circuits that regulate motivation, stress coping, and reward. Across brain regions, emerging work highlights the importance of cell type- and region-specific mechanisms that mediate ketamine's therapeutic actions. We expand on local prefrontal cortical inhibitory cellular signaling dynamics, including the interplay of various G-protein-coupled receptors (GPCRs) in cortical somatostatin interneurons and input-specific adaptations in accumbal circuits. Finally, we compare ketamine with psilocybin, an emerging therapeutic classic psychedelic for treatment-resistant depression that targets the 5-hydroxytryptamine 2A (5-HT2A) receptor primarily. A recurring theme is that an interplay of GPCRs can help shape the timing, localization, and persistence of ketamine-induced neuroplasticity. Together, these studies suggest that antidepressant efficacy arises not from a single pathway or brain region but from coordinated, temporally staged plasticity across molecules, synapses, cells, and circuits.