Regulation of N-Methyl-d-Aspartate Receptor Subunit Expression in the Fetal Guinea Pig Brain1

Abstract

N-methyl-d-aspartate receptors (NMDARs) are critical for neuronal maturation and synaptic formation as well as for the onset of long-term potentiation, a process critical to learning and memory in postnatal life. In the current study, we demonstrated that NMDAR subunits undergo spatial, temporal, and sex-specific regulation. During development, we observed increasing NR1 and NR2A expression at the same time as levels of NR2B subunits decreased in the hippocampus and cortex in the fetal guinea pig. We have also shown that glucocorticoids can modulate fetal NMDAR subunit expression in a sex-specific fashion. This is clinically important because synthetic glucocorticoids are administered to pregnant women at risk of preterm labor. Repeated exposure to exogenous glucocorticoids caused a dose-dependent decrease in NR1 mRNA levels and increased NR2A mRNA expression in the female hippocampus at Gestational Day 62. There are significant changes in NMDAR subunit expression in late gestation. It is possible that these alter NMDA-dependent signaling at this time. Prenatal exposure to exogenous glucocorticoids modifies the trajectory of NMDAR subunit expression in females but not in males.

Estradiol-Induced Increase in the Magnitude of Long-Term Potentiation Is Prevented by Blocking NR2B-Containing Receptors

“…Therefore, it is possible that these NR2B-containing receptors are in the new spines and thus are silent synapses. As synapses mature during development, synaptically located NR2B-containing receptors are replaced by receptors containing NR2A subunits coincident with an increase in currents mediated by AMPARs (Law et al, 2003;Owen et al, 2004). This is similar to what we previously have shown occurs at E72, when the fractional contribution of transmission mediated by NMDARs and AMPARs is restored to that in slices from vehicle-treated animals, although spine density and overall transmission remain elevated (Smith and McMahon, 2005).…”

RETRACTED: Maternal adversity, glucocorticoids and programming of neuroendocrine function and behaviour

“…In sheep, prenatal dexamethasone exposure in late gestation gave rise to lambs with a 20% decrease in the total number of NMDAR binding sites but no effect was observed in the late gestation fetus [177]. We have recently shown in the guinea pig that prenatal exposure to synthetic glucocorticoid results in a dose-dependent decrease in NR1 subunit mRNA, in female, but not in male fetuses [178]. The impact of early neonatal stressors and postnatal exposure to synthetic glucocorticoid on NMDAR development has been determined.…”

Repeated maternal glucocorticoid treatment affects activity and hippocampal NMDA receptor expression in juvenile guinea pigs

“…µg −1 (Owen et al 2004). Labelled probe in hybridization buffer (200 µl) was applied to slides at a concentration of 1.0 × 10 3 c.p.m.…”

“…The relative optical density (ROD) of the signal on autoradiographic film was quantified, after subtraction of background values, using a computerized image analysis system (Imaging Research Inc., St Catharines, ON, Canada) (Owen & Matthews, 2003). Levels of NMDAR subunit mRNA expression were measured in the hippocampus and cortex, as previously described (Owen et al 2004). …”

“…In animal studies, mice with mild disruption of the NMDAR exhibited increased startle reactivity but decreased aversion to a novel environment such as an open-field (Mohn et al 1999;Kew et al 2000). We have also previously shown that prenatal dexamethasone exposure markedly alters NMDAR subunit expression in the late-gestation guinea pig fetus in a sex-specific and dose-dependent manner (Owen et al 2004). Recently, studies in the spinal cord have shown direct regulation of NMDAR subunit expression by glucocorticoids (Lim et al 2005;Wang et al 2005).…”