Repeated carbenoxolone injections during late pregnancy alter Snk-SPAR and PSD-95 expression in the hippocampus of rat pups.

Homeostasis of circulating cortisol is maintained by the 11β-HSD2 enzyme which inactivates cortisol into cortisone. It is abundantly expressed in the placenta where it protects the fetus from high levels of maternal glucocorticoids (GCs). Maternal administration of Carbenoxolone (Cbx), a powerful 11β-HSD2 inhibitor, leads to an increase in fetal cortisol. Previous data showed that intrauterine environment plays a crucial role in determining hippocampal structure and function. Exposure of pregnant rats to high levels of GC leads to low birth weight in offspring and an increased risk of age related memory and cognitive deficits later in life. Glutamate receptors are localized in the postsynaptic density (PSD), where many signaling proteins, cytoskeleton proteins, and ion channels are found. Any change in the number of these molecules can influence the morphology and function of the dendritic spine. We proposed that repeated Cbx injections during late pregnancy may alter the scaffolding proteins of the NMDA receptor in the pup's brain. We investigated the effects of repeated maternal Cbx injections on the scaffolding proteins of NMDA receptor in the hippocampus of rat pups. We showed that injecting pregnant rats with Cbx injections (30mg/kg) during GD 14-21 leads to a significant decrease in SPAR (Spine Associated Rap Guanylate kinase activating protein) (p<0.001) and PSD-95 (p<0.05) but a significant increase in Snk (Serum inducible kinase) (p<0.001) in the pup's hippocampus at P40. In general, Snk is induced by neuronal activity and plays an important role in phosphorylating SPAR. The phosphorylated SPAR is then recognized and degraded by ubiquitin proteasome system (UPS), causing the depletion of SPAR and PSD-95 from the spines. The results suggest that fetal exposure to excessive GC levels may activate the Snk/SPAR pathway and lead to the depletion of SPAR and PSD-95. Since GCs drugs are commonly used in various obstetric and pediatric conditions, it is important to consider the risks and benefits of prenatal GCs exposure in order to prevent neurodevelopmental delay in the offspring.