Embryonic Ketamine Produces a Downregulation of Prefrontal Cortex NMDA Receptors and Anxiety-Like Behavior in Adult Offspring

Abstract

Previous studies have focused on the effects of N-methyl-D-aspartate receptor (NMDAR) blockade on neonates, but little is known about the effect of the embryonic NMDAR blockade on offspring, especially the long-lasting effect, on behavior in adulthood. Here, pregnant rats at E14 were treated with ketamine for 5 successive days and undergone multiple behavior tests, electrophysiology experiment, and Western blotting analysis to detect the alterations in their offspring. We found that embryonic ketamine treatment induced anxiety-like behavior in adulthood (8-week old) offspring. At the same period, we observed an attenuation of NMDA-evoked current as well as decreased NR2A and NR2B membrane expression in the prefrontal cortex (PFC), but not in the hippocampus or amygdala. Selective inhibition experiments with NR2A or NR2B specific antagonists suggested that embryonic ketamine treatment induced NMDAR current attenuation was likely mediated by changes in NR2A subunit. Moreover, at the 4-week time point, NMDA-evoked current was unchanged in PFC, but enhanced in hippocampal CA1 area, which may be caused by the over expression of NR2B in the hippocampus at 4-week time. Furthermore, NR2B knockdown, by using NR2B-shRNA lentivirus, in the hippocampal CA1 area at 3–4-week of age significantly rescued the decrease in NR2A expression in the PFC and anxiety-like behavior observed at 8-week adult offspring rats. In conclusion, our results suggested that embryonic ketamine treatment induced anxiety-like behavior and the downregulation of NMDAR function in PFC in the adulthood period of offspring, which might result from the enhanced function of NMDARs in the hippocampus at the 4-week juvenile time point.