Background IUGR predisposes to postnatal learning impairment. NMDA receptors play a role in the remodeling of synaptic conditions during postnatal development and adult associative learning. NMDA receptors are composed of a combination of NR1 and NR2 subunits, the latter of which includes NR2A and NR2B. The proportion of NR1/NR2A versus NR1/NR2B affects the function of the NMDA receptor. Yet, despite the NMDA receptors' importance in learning, little is known on how IUGR affects postnatal expression of these proteins in the brain.
Objective We hypothesized that IUGR would affect NR1, NR2A, and NR2B subunit expression in the brains of juvenile rats.
Design/Methods To induce IUGR, bilateral uterine artery ligation was performed on day 19 of gestation (term-21.5 d). Litters were culled to 6 after birth, and brain was harvested at day 21 of postnatal life. NR1, NR2A, and NR2B protein levels were quantified by Western blotting using membrane fractions. NR1, NR2A, NR2B mRNA were quantified by real-time RT-PCR (n = 6-8 litters).
Results Protein data expressed as arbitrary densitometry units ± SEM. In day 21 females, IUGR increased both NR2A protein (0.63-0.15* vs 0.34-0.06, p < .05) and NR1 protein (0.31-0.09* vs 0.14-0.01, p < .05) levels, whereas NR2B protein levels were decreased in the IUGR brain (0.39-0.04* vs 0.59-0.04, p < .0001). Day 21 males were no different from controls. mRNA data expressed as percent of control ± SEM. Interestingly, mRNA levels of all three genes were increased relative to control in both genders: NR1A mRNA (male: 122 + 8.7%*; female: 112 + 5.8%*), NR2A mRNA (male: 115 + 7.2%*; female: 144 + 7.6 %**), NR2B (male: 119 + 3.7%**; female: 121 + 6.3 %**) (*p < .05; **p < .01).
Conclusions IUGR increased membrane protein levels of NR1 and NR2A subunits in female IUGR rat brains, whereas mRNA levels of all three subunit were increased in both genders. These results are intriguing because IUGR rats are characterized by increased levels of glucocorticoids, which previous studies demonstrate up-regulate female NR1 and NR2A cerebral expression but not male. We speculate that the increased levels of NR1 and NR2A subunits in the female IUGR brains may be due to gender-specific steroid-induced affect upon protein translation or stability.
Supported by CHRC, March of Dimes.
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