The hippocampus as a central hub in ketamine's antidepressant action: from molecules to circuit rewiring.
Dongsun Park, Gwangho Lee, Bokyum Kim, Minjoo Seong, Ji-Woon Kim
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology February 1, 2026 Peer reviewed DOI: 10.1038/s41386-025-02288-9 via PubMed
Summary
Ketamine enhances hippocampal synaptic plasticity, leading to rapid and sustained antidepressant effects. It works through mechanisms such as NMDAR blockade, BDNF-TrkB signaling, and adult neurogenesis. The review emphasizes that these effects are linked with broader brain network interactions, particularly involving the medial prefrontal cortex and lateral habenula, rather than traditional neuroendocrine models. This suggests a new understanding of how ketamine functions as an antidepressant.
Study at a glance
| Design | review |
|---|---|
| Key finding | Ketamine enhances hippocampal synaptic plasticity through various mechanisms, facilitating both rapid and sustained antidepressant effects. |
Abstract
Ketamine has emerged as a rapid-acting antidepressant that challenges classical monoaminergic frameworks and highlights the importance of synaptic and circuit-level plasticity in mood regulation. This review examines the hippocampus as a key site through which ketamine exerts both rapid and sustained antidepressant effects. We synthesize evidence showing that ketamine enhances hippocampal synaptic plasticity via mechanisms including NMDAR blockade of spontaneous neurotransmission, BDNF-TrkB signaling, MeCP2-dependent transcriptional priming, and adult neurogenesis. Molecular modulators such as Reelin, which influence NMDAR signaling and synaptic function, may also shape the efficacy of ketamine in a subset of individuals. Importantly, these hippocampal effects occur in coordination with broader network interactions, particularly with the medial prefrontal cortex and lateral habenula, allowing for circuit-level integration of antidepressant responses. Notably, ketamine's therapeutic actions are dissociable from normalization of hypothalamic-pituitary-adrenal (HPA) axis function, underscoring a shift away from neuroendocrine-based models. By integrating molecular, synaptic, and systems-level findings, this review provides a hippocampus-centered framework for understanding ketamine's antidepressant mechanisms and outlines novel strategies for circuit-informed, fast-acting antidepressant development.