Prenatal stress induced gender-specific alterations of N-methyl-d-aspartate receptor subunit expression and response to Aβ in offspring hippocampal cells

Abstract

Prenatal stress (PS) is one of adverse life events during pregnancy, which may increase vulnerability to cognitive impairment in adult offspring. Aβ synaptotoxicity is one important pathological factor for cognitive impairment, and PS-induced cognitive disorder is closely associated with N-Methyl-d-Aspartate receptor (NMDAR), which acts as a key mediator of Aβ synaptotoxicity. In the present study, we tried to explore whether PS affects offspring’s Aβ levels and NMDAR subunit expression in a gender-specific manner in hippocampal CA and DG subregions, and whether PS affects synaptic proteins and NMDAR subunit expression in cultured offspring hippocampal cells exposed to Aβ. Pregnant SD rats with restraint stress from gestation day 8–20 were used as PS model. Morris water maze, ELISA, immunofluorescence and western blot were tested on postnatal day 90 in male and female PS offspring. Our results showed that female offspring is more vulnerable to PS-induced cognitive impairment. Surprisingly, PS enhanced Aβ1-40 levels in the hippocampal DG subregion of male offspring. Furthermore, WB results implied that the decreased GluN2A in CA of female may contribute to the PS-induced cognitive impairment, while in DG, the increased GluN2A and decreased GluN2B contributed to protective effects against Aβ. Interestingly, we found PS could alleviate Aβ synaptotoxicity in male offspring’s hippocampal cells. Overall, our results provided a fundamental understanding of PS-induced gender-specific alterations of NMDAR subunit expression and the susceptibility to Aβ, and paved the road for the development of timely preventive interventions on cognitive disorders of PS offspring.