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 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.

Impaired Cell Cycle Progression and Self-Renewal of Fetal Neural Stem and Progenitor Cells in a Murine Model of Intrauterine Growth Restriction

“…However, numerous rodent studies using uterine artery ligation or hypoxia exposure of the pregnant dams have established the association between IUGR and impaired cognitive function, recapitulating clinical observations of increased risks of neurodevelopmental impairment among individuals with IUGR and small for gestational age ( Dubrovskaya and Zhuravin, 2010 ; Delcour et al, 2012 ; Sab et al, 2013 ; Howell and Pillai, 2014 ). Similar to our study, a recent study used thromboxane A 2 to induce IUGR in mice and found deficits in hippocampal dentate gyrus neurogenesis as well as in short-term adult learning and memory ( Brown et al, 2021 ).…”

Effects of Low-Dose Aspirin Combined with Vitamin E on the Incidence of Intrauterine Growth Restriction and Hemorheological Indexes of Pregnant Women in Patients with Gestational Hypertension

“…Following up children with intrauterine growth restriction, most infants and young children will have excessive weight gain, also known as compensatory growth [ 23 ]. Therefore, intrauterine growth restriction is a risk factor for late obesity [ 24 ].…”

Intrauterine Growth Restriction Disrupts the Postnatal Critical Period of Synaptic Plasticity in the Mouse Dorsal Hippocampus in a Model of Hypertensive Disease of Pregnancy

“…In the hippocampus, IUGR produces hypoplasia and reduced number and dendritic complexity of neurons [12-15]. IUGR models that produce a hypertensive-like phenotype in pregnancy mirror these human findings by replicating hippocampal hypoplasia [16] and hippocampal-dependent memory deficits [17-19], which are common in neurodevelopmental disorders and psychopathologies [20, 21]. However, the mechanisms underlying these structural and functional deficits need further investigation.…”

“…First, the hippocampus has a well-defined CPd of synaptic plasticity [24, 25, 35-38] improving our ability to interpret our data. Second, hippocampal hypoplasia and dysfunction, as seen in our model [16], have been characterized in patients with IUGR [17] and those with schizophrenia [20, 21]. Thus, studying the molecular alterations in the events governing the hippocampal CPd will improve our ability to make meaningful contributions about the mechanistic origins of neurodevelopmental disorders and psychopathology in IUGR patients.…”