Human infants who suffer from intrauterine growth restriction (IUGR), which is a failure to attain their genetically predetermined weight, are at increased risk for postnatal learning and memory deficits. Hippocampal dentate gyrus (DG) granule neurons play an important role in memory formation; however, it is unknown whether IUGR affects embryonic DG neurogenesis, which could provide a potential mechanism underlying abnormal postnatal learning and memory function. Using a mouse model of the most common cause of IUGR, induced by hypertensive disease of pregnancy, we first assessed adult learning and memory function. We quantified the percentages of embryonic hippocampal DG neural stem cells (NSCs) and progenitor cells and developing glutamatergic granule neurons, as well as hippocampal volumes and neuron cell count and morphology 18 and 40 d after delivery. We characterized the differential embryonic hippocampal transcriptomic pathways between appropriately grown and IUGR mouse offspring. We found that IUGR offspring of both sexes had short-term adult learning and memory deficits. Prenatally, we found that IUGR caused accelerated embryonic DG neurogenesis and Sox2 + neural stem cell depletion. IUGR mice were marked by decreased hippocampal volumes and decreased doublecortin + neuronal progenitors with increased mean dendritic lengths at postnatal day 18. Consistent with its known molecular role in embryonic DG neurogenesis, we also found evidence for decreased Wnt pathway activity during IUGR. In conclusion, we have discovered that postnatal memory deficits are associated with accelerated NSC differentiation and maturation into glutamatergic granule neurons following IUGR, a phenotype that could be explained by decreased embryonic Wnt signaling.

BackgroundChildren 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.MethodsUsing 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.ResultsWe 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.ConclusionWe have discovered that postnatal memory deficits are associated with accelerated NSPC differentiation following IUGR, a phenotype that could be explained by decreased Wnt signaling.