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The hippocampus as a central hub in ketamine’s antidepressant action: from molecules to circuit rewiring

Neuropsychopharmacology volume 51, pages 537–547 (2026)Cite this article

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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.

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Fig. 1: The hippocampus as a central hub for mood regulation.
Fig. 2: Comparison of Hebbian and homeostatic synaptic plasticity.

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Acknowledgement

This work was supported by a grant from the BK21 FOUR program of Graduate School, Kyung Hee University (KHU-20250488 to D.P.), the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (RS-2023-00212118 and RS-2025-02217139 to JK), Ministry of Food and Drug safety in 2025 (RS-2024-00397713 to JK), the Korea Dementia Research Project through the Korea Dementia Research Center(KDRC), funded by the Ministry of Health & Welfare and Ministry of Science and ICT, Republic of Korea (grant number : RS-2025-02253017), and Kyung Hee University in 2022 (KHU-20222245 to JK).

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  1. These authors contributed equally: Dongsun Park, Gwangho Lee.

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  1. Department of Biomedical and Pharmaceutical science, College of Pharmacy, Graduate School, Kyung Hee University, Seoul, Republic of Korea

    Dongsun Park & Ji-Woon Kim

  2. Institute of Integrated Pharmaceutical Science, Kyung Hee University, Seoul, Republic of Korea

    Dongsun Park, Gwangho Lee, Bokyum Kim, Minjoo Seong & Ji-Woon Kim

  3. Department of Regulatory Science, College of Pharmacy, Graduate School, Kyung Hee University, Seoul, Republic of Korea

    Gwangho Lee, Bokyum Kim, Minjoo Seong & Ji-Woon Kim

  4. Institute of Regulatory innovation through Science, Kyung Hee University, Seoul, Republic of Korea

    Ji-Woon Kim

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Park, D., Lee, G., Kim, B. et al. The hippocampus as a central hub in ketamine’s antidepressant action: from molecules to circuit rewiring. Neuropsychopharmacol. 51, 537–547 (2026). https://doi.org/10.1038/s41386-025-02288-9

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