地塞米松被广泛用于防治多种早产相关疾病，但治疗量可引起子代神经发育毒性。我们新近发现，孕期地塞米松暴露(PDE)可致子代大鼠学习记忆障碍，但确切机制不清。通过高通量测序和验证检测，我们发现PDE子代大鼠出生前后海马miR-133a-3p显著上调，伴随其靶基因组蛋白去乙酰化酶SIRT1表达抑制和细胞周期素依赖蛋白激酶Cdk5组蛋白高乙酰化/高表达。综合预实验和文献报道，我们推测：PDE通过调控胎海马miR-133a-3p/SIRT1/Cdk5级联改变，增加谷氨酸受体NR2B磷酸化并减少其膜移位，抑制海马兴奋性突触传递。这种miR-133a-3p介导的编程性变化可延续到出生后，导致成年学习记忆障碍发生。本项目拟通过动物、细胞及临床标本阐明PDE子代学习记忆障碍的宫内编程机制，确证miR-133a-3p可能作为胎源性学习记忆障碍的早期预警标志物，为指导孕期合理用药并探寻早期防治策略提供实验依据。

Dexamethasone is widely used to prevent and treat a variety of preterm birth related-diseases, but the treatment dose can cause neurodevelopmental toxicity in offspring. We recently found that prenatal dexamethasone exposure (PDE) can cause learning and memory impairment in offspring rats, but the exact mechanism is unclear. Through high-throughput sequencing and validation, we found that miR-133a-3p was significantly up-regulated in the hippocampus of PDE offspring rats before and after birth, accompanied by inhibited expression of its target gene histone acetylation enzyme—SIRT1 and high histone acetylation/expression of cyclin-dependent protein kinase Cdk5. Based on preliminary experiments and literature reports, we speculated that PDE inhibits excitatory synaptic transmission in the hippocampus by regulating the cascade changes of fetal hippocampal miR-133a-3p/SIRT1/Cdk5, increasing the phosphorylation of glutamate receptor NR2B and reducing its membrane displacement. Such programming changes mediated by miR-133a-3p can continue after birth and lead to learning and memory disorders in adults. This project intends to elucidate the intrauterine programming mechanism of PDE induced learning and memory disorders in offspring through animal, cell and clinical experiment, and confirm that miR-133a-3p may be used as an early warning marker of fetal originated learning and memory disorders, so as to provide experimental basis for guiding rational drug use during pregnancy and exploring early prevention and treatment strategies.