Intrauterine Growth Restriction Impairs Hippocampal Neurogenesis and Cognition via Tet1/Notch signaling in Offspring

Intrauterine growth restriction (IUGR) increases the risk of cognitive impairments in offspring in later life. However, the precise mechanisms underlying this process remain elusive. Here, we used two IUGR mouse models and observed learning and memory deficits in adult IUGR offspring. IUGR induces decreased hippocampal neurogenesis from the early postnatal period to adulthood by reducing the proliferation of neural stem cells (NSCs). Mechanistically, persistently decreased Tet1 in hippocampal NSCs induces the inhibition of Notch signaling. Overexpression of Tet1 activates Notch signaling, offsets the decline in neurogenesis, and enhances learning and memory abilities in IUGR offspring, which provides potential new targets for improving the long-term cognitive outcomes of IUGR.宫内生长受限（Intrauterine growth restriction, IUGR）会增加子代晚年出现认知功能障碍的风险。然而，介导这一病理过程的确切分子机制仍尚不明确。本研究采用两种宫内生长受限小鼠模型，观察到成年子代小鼠出现了学习记忆功能缺陷。宫内生长受限可通过降低神经干细胞（neural stem cells, NSCs）的增殖活性，从出生早期至成年阶段抑制海马神经发生。从机制层面分析，海马神经干细胞中Tet1的持续表达下调会抑制Notch信号通路。过表达Tet1可激活Notch信号通路，抵消神经发生的衰退，并改善宫内生长受限子代小鼠的学习记忆能力，该发现为改善宫内生长受限子代的长期认知预后提供了潜在的全新干预靶点。