Dong Jianfeng, Chen Wen, Chang Shujuan, Liu Nana, Zhu Wei, Ma Li, Qiao Jing, Wang Yuhang, Mao Zhiyong, Kang Jiuhong
Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, National Stem Cell Translational Resource Center, School of Life Sciences and Technology, Tongji University, Shanghai, China.
Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Shanghai Key Laboratory of Maternal Fetal Medicine, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, China.
FASEB J. 2025 Jun 15;39(11):e70691. doi: 10.1096/fj.202402934R.
Infants born with fetal growth restriction (FGR) are at increased risk of cognitive impairment in later life, yet the underlying mechanisms remain poorly understood, hampering clinical treatment development. Utilizing a FGR mouse model induced by prenatal dexamethasone overexposure, we observed impaired hippocampal dendritic maturation, synaptic plasticity, and hippocampal-dependent learning and memory in FGR mice. FGR induces DNA hypomethylation in the hippocampal H19/Igf2 imprinted control region, resulting in reduced expression of Igf2, a key metabolic modulator previously implicated in FGR-related placental and fetal growth. Using a neuron-specific knockout mouse model, we validated the necessity of Igf2 for dendritic maturation and synaptic plasticity. Importantly, overexpression of Igf2 in the hippocampus of FGR mice improved synaptic plasticity and enhanced learning and memory abilities. Furthermore, running exercise ameliorated DNA hypomethylation driving Igf2 expression levels and counteracted synaptic and cognitive deficits in FGR mice through hippocampal Igf2. These findings unveil a molecular mechanism linking exercise-induced epigenetic changes in the imprinting gene Igf2 to enhanced synaptic plasticity, ultimately leading to improved cognition in FGR offspring. Our results identify Igf2 as a potential mediator bridging metabolic dysfunction and cognitive impairments in FGR offspring and also propose that exercise represents a promising nondrug intervention for FGR-related cognitive disorders.
出生时患有胎儿生长受限（FGR）的婴儿在以后的生活中出现认知障碍的风险增加，但其潜在机制仍知之甚少，这阻碍了临床治疗的发展。利用产前地塞米松过度暴露诱导的FGR小鼠模型，我们观察到FGR小鼠海马树突成熟、突触可塑性以及海马依赖性学习和记忆受损。FGR诱导海马H19/Igf2印记控制区域的DNA低甲基化，导致Igf2表达降低，Igf2是一种关键的代谢调节因子，先前与FGR相关的胎盘和胎儿生长有关。使用神经元特异性敲除小鼠模型，我们验证了Igf2对树突成熟和突触可塑性的必要性。重要的是，在FGR小鼠海马中过表达Igf2可改善突触可塑性并增强学习和记忆能力。此外，跑步运动改善了驱动Igf2表达水平的DNA低甲基化，并通过海马Igf2抵消了FGR小鼠的突触和认知缺陷。这些发现揭示了一种分子机制，将运动诱导的印记基因Igf2的表观遗传变化与增强的突触可塑性联系起来，最终改善FGR后代的认知。我们的结果确定Igf2是连接FGR后代代谢功能障碍和认知障碍的潜在介质，并提出运动是一种有前景的针对FGR相关认知障碍的非药物干预措施。
