S-ketamine alleviates depression-like behavior and hippocampal neuroplasticity in the offspring of mice that experience prenatal stress.
Yan Zhang, Chu-Ke Wei, Ping Wang, Liu-Cheng Zheng, Yang Cheng, Zhen-Hua Ren, Yu-Hong Jin, Yu-You Yao, Huan-Zhong Liu
Scientific Reports November 6, 2024 DOI: 10.1038/s41598-024-76226-y (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Animal study Peer reviewed |
|---|---|
| Population | Male offspring of pregnant rats subjected to chronic unpredictable mild stress |
| Intervention | S-ketamine |
| Dose | 10 mg/kg |
| Duration | Single dose on postnatal day 42 |
| Topics | Depression Esketamine Neuroplasticity Ketamine |
| Keywords | Hippocampus Offspring Prenatal stress Prenatal-stress Depression-treatment Brain-development Mental-health |
| Citations | 12 |
| Key points | S-ketamine alleviates depression-like behaviors and enhances hippocampal neuroplasticity in prenatally stressed male offspring via the BDNF/AKT/mTOR signaling pathway. |
Abstract
Prenatal stress exerts long-term impact on neurodevelopment in the offspring, with consequences such as increasing the offspring's risk of depression in adolescence and early adulthood. S-ketamine can produce rapid and robust antidepressant effects, but it is not clear yet whether and how S-ketamine alleviates depression in prenatally stressed offspring. The current study incestigated the preliminary anti-depression mechanism of S-ketamine in prenatally stressed offspring, particularly with regard to neuroplasticity. The pregnant females were given chronic unpredictable mild stress on the 7th-20th day of pregnancy and their male offspring were intraperitoneally injected with a single dose of S-ketamine (10 mg/kg) on postnatal day 42. Our findings showed that S-ketamine treatment counteracted the development of depression-like behaviors in prenatally stressed offspring. At the cellular level, S-ketamine markedly enhanced neuroplasticity in the CA1 hippocampus: Golgi-Cox staining showed that S-ketamine alleviated the reduction of neuronal complexity and dendritic spine density; Transmission electron microscopy indicated that S-ketamine reversed synaptic morphology alterations. At the molecular level, by western blot and RT-PCR we detected that S-ketamine significantly upregulated the expression of BDNF and PSD95 and activated AKT and mTOR in the hippocampus. In conclusion, prenatal stress induced by chronic unpredictable mild stress leads to depressive-like behaviors and hippocampal neuroplasticity impairments in male offspring. S-ketamine can produce antidepressant effects by enhancing hippocampal neuroplasticity via the BDNF/AKT/mTOR signaling pathway.
Comparable studies
Other preclinical and animal studies on esketamine for depression, most cited first.
Citations in the library
Cited by 4
- The hippocampus as a central hub in ketamine's antidepressant action: from molecules to circuit rewiring. Neuropsychopharmacology February 1, 2026
- Quantitative monitoring of ketamine's impact on synaptic density using 11C-UCB-J PET imaging in the corticosterone mouse model of anxiety/depression. Molecular Psychiatry November 18, 2025
- Hippocampal subfield differences in people with and without recreational ketamine use: Insights from multi-modal neuroimaging. Addiction January 29, 2026
- A systematic review of ketamine's anxiolytic potential in rodent behavioral models of anxiety and PTSD. Pharmacology, Biochemistry, and Behavior February 2026
Cites 14
- mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Science August 19, 2010
- Synaptic Dysfunction in Depression: Potential Therapeutic Targets Science October 4, 2012
- Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression JAMA Psychiatry June 5, 2019
- Efficacy and Safety of Intranasal Esketamine for the Rapid Reduction of Symptoms of Depression and Suicidality in Patients at Imminent Risk for Suicide: Results of a Double-Blind, Randomized, Placebo-Controlled Study American Journal of Psychiatry April 16, 2018
- R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Translational Psychiatry September 1, 2015
and 9 more in the library