Intrauterine growth restriction causes abnormal embryonic dentate gyrus neurogenesis in mouse offspring that leads to adult learning and memory deficits

Abstract

Human infants who suffer from intrauterine growth restriction (IUGR), which is a failure to attain their genetically pre-determined 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 and progenitor cells and developing glutamatergic granule neurons, as well as hippocampal volumes and neuron cell count and morphology 18 and 40 days 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 (P) 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.

Significance Statement

Postnatal learning and memory deficits are common in infants born with IUGR. However, the embryonic cellular and molecular hippocampal changes are elusive compared to the many postnatal studies in the literature. Using a translationally relevant mouse model with short-term memory deficits, we discovered that IUGR accelerated embryonic hippocampal DG neurogenesis along with NSC depletion. Decreased postnatal hippocampal volumes with altered neuronal progenitor development were noted. Transcriptomic analysis revealed decreased Wnt signaling as a strong candidate for embryonic cellular changes after IUGR. To our knowledge, this is the first investigation linking IUGR-induced embryonic hippocampal DG alterations with postnatal neuronal developmental aberrations. This model provides a framework to investigate other hippocampal domains and cell types that modulate neuronal maturation and memory function.