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

Abstract

Introduction: Intrauterine growth restriction (IUGR) from hypertensive disease of pregnancy complicates up to 10% of all pregnancies. Significant hippocampal-dependent cognitive and memory impairments as well as neuropsychiatric disorders have been linked to IUGR. Because disturbance of hippocampal critical period (CPd) of synaptic plasticity leads to impairments similar to those described in IUGR human offspring, we hypothesized that IUGR would perturb the CPd of synaptic plasticity in the mouse hippocampus in our model. Methods: IUGR was produced by a micro-osmotic pump infusion of the potent vasoconstrictor U-46619, a thromboxane A2-agonist (TXA2), at embryonic day (E) 12.5 in C57BL/6J mouse dams to precipitate hypertensive disease of pregnancy and IUGR. Sham-operated mice acted as controls. At P10, P18, and P40, we assessed astrogliosis using GFAP-IHC. In dorsal CA1 and CA3 subfields, we assessed the immunoreactivities (IR) (IF-IHC) to: i) parvalbumin (PV) and glutamate decarboxylase (GAD) 65/67, involved in CPd onset; ii) PSA-NCAM, that antagonizes CPd onset; iii) NPTX2, necessary for excitatory synapse formation and engagement of CPd; and iv) MBP and WFA, staining perineural nets (PNNs), marking CPd closure. ImageJ/Fiji and IMARIS were used for image processing and SPSS v24 for statistical analysis. Results: Although PV+ interneuron (IN) numbers and IR intensity were unchanged, development of GAD65/67+ synaptic boutons was accelerated at P18 IUGR mice, and inversely correlated with decreased expression of PSA-NCAM in the CA of P18 IUGR mice at P18. NPTX2 + puncta and total volume were persistently decreased in the CA3 pyramidal and radiatum layers of IUGR mice from P18 to P40. At P40, axonal myelination (MBP+) in CA3 of IUGR mice was decreased and correlated with NPTX2 deficits. Lastly, the volume and integrity of the PNNs in the dorsal CA was disrupted in IUGR mice at P40. Discussion/Conclusion: IUGR disrupts the molecular and structural initiation, consolidation and closure of the CPd of synaptic plasticity in the mouse hippocampus in our model, which may explain the learning and memory deficits observed in juvenile IUGR mice and the cognitive disorders seen in human IUGR offspring. The mechanistic links warrant further investigation, to identify therapeutic targets to prevent neurodevelopmental deficits in patients affected by IUGR.

Effects of intrauterine growth restriction on embryonic hippocampal dentate gyrus neurogenesis and postnatal critical period of synaptic plasticity that govern learning and memory function

“…In our mouse model, we examined these phases of the critical period at P10, P18, and P40. We found that at P10, no difference was seen in the number or volume of either PV + interneurons or GAD 65/67 + puncta between sham and IUGR (St Pierre et al, 2022). At P18, however, despite no difference in PV + interneurons, we found increased GAD 65/67 + puncta and volume in IUGR mice in CA pyramidal cell layer compared to sham, suggesting an advanced GABAergic development in IUGR.…”

“…At P18, however, despite no difference in PV + interneurons, we found increased GAD 65/67 + puncta and volume in IUGR mice in CA pyramidal cell layer compared to sham, suggesting an advanced GABAergic development in IUGR. At P40, this difference disappeared in IUGR as the sham group caught up in GAD + bouton development (St Pierre et al, 2022). Concurrently at P18, we saw decreased PSA-NCAM expression in the pyramidal cell membranes in IUGR, which normally acts to limit the formation of perisomatic inhibitory GABAergic synapses, but in this case has permitted the accelerated GABAergic synaptic formation in IUGR mice.…”

“…Since the classical experiments performed by Hubel and Wiesel in the visual cortex in the 1960s (Hubel and Wiesel, 1962;Wiesel and Hubel, 1963), it has been well accepted that a critical period exists when neurons are particularly susceptible to modification by experience, which is concurrent with large-scale anatomical changes that become irreversible after the closure of this critical period (Hensch, 2004(Hensch, , 2005St Pierre et al, 2022). The classical critical period of plasticity occurs mostly in juvenile animals.…”

“…It has been considered as a central mechanism for establishing fine-tuned neuronal circuits in the developing brain characterized by profound refinement and remodeling of brain circuits with extensive neurite outgrowth, synaptic formation, and pruning to create mature networks shaped by experience (Hensch, 2004(Hensch, , 2005. The critical period in the dorsal hippocampal CA subregions, marked by boundaries that are determined by complex biochemical and structural events between the excitatory pyramidal cells and the inhibitory parvalbumin + (PV + ) interneurons, strives to create an excitatory to inhibitory balance (St Pierre et al, 2022). The opening of this critical period is governed by decreased polysialylation of the neural cell adhesion molecule (PSA-NCAM) in the excitatory pyramidal neuronal membranes as well as advanced maturation of PV + interneurons with increased number of glutamate decarboxylase (GAD) synaptic boutons/axon terminals to result in GABAergic network development (Figure 3A; Lisman et al, 2012;Travaglia et al, 2016a,b).…”

Highlighting the trajectory from intrauterine growth restriction to future obesity

“…This could be explained by disturbed prenatal neuronal development. St. Pierre et al were able to demonstrate in a murine IUGR model that IUGR is associated with impaired synaptic plasticity in the hippocampus (133). In addition, Brown et al described that IUGR mice show a reduced number of neural stem cells in the hippocampus as well as a disturbed induction of neuronal differentiation.…”