Intrauterine growth restriction due to uteroplacental insufficiency decreased white matter and altered NMDAR subunit composition in juvenile rat hippocampi

Abstract

Uteroplacental insufficiency (UPI), the major cause of intrauterine growth restriction (IUGR) in developed nations, predisposes to learning impairment. The underlying mechanism is unknown. Neuronal N-methyl-d-aspartate receptors (NMDARs) are critical for synaptogenesis and learning throughout life. We hypothesized that UPI-induced IUGR alters rat hippocampal NMDAR NR2A/NR2B subunit ratio and/or NR1 mRNA isoform expression and synaptic density at day 21 (P21). To test this hypothesis, IUGR was induced by bilateral uterine artery ligation of the late-gestation Sprague-Dawley dam. At P21, hippocampal NMDAR subunit mRNA and protein were measured, as were levels of synaptophysin. Neuronal, synaptic, and glial density in CA1, CA3, and dentate gyrus (DG) was assessed by immunofluorescence. IUGR increased NR1 mRNA isoform NR1-3a and 1-3b expression in both sexes. In P21 males, IUGR increased protein levels of NR1 C2' and decreased NR1 C2, NR2A, and the NR2A-to-NR2B ratio, whereas in females, IUGR increased NR2B protein. In males, IUGR was associated with decreased myelin basic protein-to-neuronal nuclei ratio in CA1, CA3, and DG. We conclude that IUGR has sex-specific effects and that neither neuronal loss nor decreased synaptic density appears to account for the changes in NMDAR subunits. Rather, it is possible that synaptic NMDAR subunit composition is altered. Our results suggest that apparent recovery in the IUGR hippocampus may be associated with synaptic hyperexcitability. We speculate that the NMDAR plays an important role in IUGR-associated cognitive impairment.

Synaptic Development and Neuronal Myelination Are Altered with Growth Restriction in Fetal Guinea Pigs

“…Given the extent that myelination and synaptogenesis impact one another, it is not surprising that related decreases in myelination were evident in dorsal FOR and FIM neurons leading from hippocampal subareas that have experienced blunted synaptogenesis. The reduced myelination observed in the present study corroborates results from a study by Schober et al [57] which found reduced myelination in hippocampal subareas in 21-day-old rats growth restricted by placental insufficiency. Myelination, as measured by MBP-IR and/or LFB staining, was also reduced in the parasagittal and PVW, as well as the CC in FGR animals (more so with sFGR than aFGR).…”

Protective effects of maternal nutritional supplementation with lactoferrin on growth and brain metabolism

“…N-methyl-D-aspartate receptors are centrally involved in hippocampal synaptic plasticity (34) and seem to be selectively targeted in the IUGR situation. Altered composition of glutamate receptor subunits was recently observed in the hippocampus of IUGR rats born from an uteroplacental insufficiency model (35) and N-methyl-Daspartate receptor subtype 2B (Grin2b) was increased in the hippocampus of prenatally stressed rats (36). Microarrays allowed us to deeper characterize the hippocampal transcriptomic hallmark in DEX-IUGR pups as well as the impact of maternal bLf.…”

Gestational-neonatal iron deficiency suppresses and iron treatment reactivates IGF signaling in developing rat hippocampus

“…7), may have implications for other early nutrient deficiencies, including copper deficiency, iodine/thyroid hormone deficiency, and the proteinenergy malnutrition found in intrauterine growth restriction. All are characterized by hypomyelination and abnormal cognitive function and are interrelated; copper deficiency induces iron deficiency, whereas both induce a hypothyroid state in the brain (4,25,54,55). Although iron deficiency is common to these perinatal nutrient deficiencies (4,50), the similarity of brain developmental defects suggests that hippocampal IGF signaling is likely impaired in all of these preclinical rodent models.…”