Insulin‐Like Growth Factor 2 Reverses Synaptic and Cognitive Deficits in Fetal Growth Restriction Mice

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. Fetal growth restriction (FGR) induces hippocampal DNA hypomethylation and loss of Igf2, contributing to impaired synaptic plasticity and cognitive deficits in offspring. Exercise restores Igf2 levels and rescues these impairments, suggesting a potential therapeutic strategy for FGR‐related cognitive dysfunction.