S-ketamine alleviates depression-like behavior and hippocampal neuroplasticity in the offspring of mice that experience prenatal stress.

Publisher: Nature Publishing Group Country of Publication: England NLM ID: 101563288 Publication Model: Electronic Cited Medium: Internet ISSN: 2045-2322 (Electronic) Linking ISSN: 20452322 NLM ISO Abbreviation: Sci Rep Subsets: MEDLINE

Original Publication: London : Nature Publishing Group, copyright 2011-

Ketamine*/pharmacology ; Neuronal Plasticity*/drug effects ; Prenatal Exposure Delayed Effects* ; Depression*/drug therapy ; Stress, Psychological*/drug therapy ; Stress, Psychological*/complications ; Hippocampus*/drug effects ; Hippocampus*/metabolism ; Antidepressive Agents*/pharmacology; Animals ; Female ; Pregnancy ; Mice ; Male ; Behavior, Animal/drug effects ; Brain-Derived Neurotrophic Factor/metabolism ; Brain-Derived Neurotrophic Factor/genetics ; TOR Serine-Threonine Kinases/metabolism ; Disease Models, Animal

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.
(© 2024. The Author(s).)

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81773452 National Natural Science Foundation of China

Keywords: Depression; Hippocampus; Neuroplasticity; Offspring; Prenatal stress; S-ketamine

690G0D6V8H (Ketamine)
0 (Antidepressive Agents)
50LFG02TXD (Esketamine)
0 (Brain-Derived Neurotrophic Factor)
EC 2.7.11.1 (TOR Serine-Threonine Kinases)

Date Created: 20241106 Date Completed: 20241106 Latest Revision: 20241109

20250114

PMC11542010

10.1038/s41598-024-76226-y

39505897