A single prenatal lipopolysaccharide injection has acute, but not long-lasting, effects on cerebral kynurenine pathway metabolism in mice.

Abstract

In rodents, a single injection of lipopolysaccharide (LPS) during gestation causes chemical and functional abnormalities in the offspring. These effects may involve changes in the kynurenine pathway (KP) of tryptophan degradation and may provide insights into the pathophysiology of psychiatric diseases. Using CD1 mice, we examined acute and long-term effects of prenatal LPS treatment on the levels of kynurenine and its neuroactive downstream products kynurenic acid (KYNA), 3-hydroxykynurenine (3-HK) and quinolinic acid. To this end, LPS (100 μg/kg, i.p.) was administered on gestational day 15, and KP metabolites were measured 4 and 24 h later or in adulthood. After 4h, kynurenine, KYNA and 3-HK levels were elevated in the fetal brain, 3-HK and KYNA levels were increased in the maternal plasma, and kynurenine was increased in the maternal brain, whereas no changes were seen in the placenta. These effects were less prominent after 24 h, and prenatal LPS did not affect the basal levels of KP metabolites in the forebrain of adult animals. In addition, a second LPS injection (1mg/kg) in adulthood in the offspring of prenatally saline- and LPS-treated mice caused a similar elevation in 3-HK levels in both groups after 24 h, but the effect was significantly more pronounced in male mice. Thus, acute immune activation during pregnancy has only short-lasting effects on KP metabolism and does not cause cerebral KP metabolites to be disproportionally affected by a second immune challenge in adulthood. However, prenatal KYNA elevations still contribute to functional abnormalities in the offspring.