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

S-氯胺酮可减轻经历产前应激的小鼠后代的抑郁样行为和海马神经可塑性

Authors: Yan Zhang, Chu-Ke Wei, Ping Wang, Liu-Cheng Zheng, Yang Cheng, Zhen-Hua Ren, Yu-Hong Jin, Yu-You Yao, Huan-Zhong Liu.

Source: Sci Rep. 2024 Nov 6;14(1):26929.doi: 10.1038/s41598-024-76226-y. 

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.

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

摘要

产前压力对后代的神经发育产生长期影响，其后果包括增加后代在青春期和成年早期患抑郁症的风险。S-氯胺酮可以产生快速而强大的抗抑郁作用，但目前尚不清楚 S-氯胺酮是否以及如何缓解产前应激后代的抑郁。目前的研究强调了 S-氯胺酮在产前应激后代中的初步抗抑郁机制，特别是在神经可塑性方面。怀孕女性在怀孕第 7-20 天给予慢性不可预测的轻度应激，其雄性后代在出生后第 42 天腹腔注射单剂量 S-氯胺酮（10 mg/kg）。我们的研究结果表明，S-氯胺酮治疗抵消了产前应激后代抑郁样行为的发展。在细胞水平上，S-氯胺酮显着增强了 CA1 海马体的神经可塑性：高尔基体-Cox 染色显示 S-氯胺酮减轻了神经元复杂性和树突棘密度的降低;透射电子显微镜表明 S-氯胺酮逆转突触形态改变。在分子水平上，通过 western blot 和 RT-PCR，我们检测到 S-氯胺酮显着上调海马中 BDNF 和 PSD95 的表达，并激活 AKT 和 mTOR。总之，慢性不可预测的轻度压力诱导的产前应激导致雄性后代出现抑郁样行为和海马神经可塑性损伤。S-氯胺酮可通过 BDNF/AKT/mTOR 信号通路增强海马神经可塑性，从而产生抗抑郁作用。

关键字： 抑郁症;海马体;神经可塑性;后代;产前压力;S-氯胺酮。