Intrauterine growth restriction causes cellular, molecular, and behavioral deficits consistent with abnormal dentate gyrus neurogenesis in mice

Background: Children born with intrauterine growth restriction (IUGR) are at increased risk for cognitive impairment including learning and memory deficits. Dentate gyrus (DG) granule neurons relay cortical information into the hippocampus proper for memory formation, and their production is highly dependent on environmental signals. However, it is unknown whether IUGR affects DG neurogenesis, and thus provides a potential mechanism underlying abnormal learning and memory function. Methods: Using a hypertensive disease of pregnancy mouse model of IUGR, we assessed multiple behaviors, quantified neural stem and progenitor cells (NSPCs) and developing neurons in the DG, and characterized transcriptional effects on molecular pathways in the hippocampus. Results: We found that the predominant behavioral phenotype in IUGR offspring, short-term implicit learning and memory deficits, was associated with accelerated DG neurogenesis and NSPC depletion. Consistent with known molecular regulators of DG neurogenesis, we also found strong evidence for decreased Wnt pathway activity following IUGR. Conclusion: We have discovered that postnatal memory deficits are associated with accelerated NSPC differentiation following IUGR, a phenotype that could be explained by decreased Wnt signaling.