Sex-Specific Neuropsychiatric Effects of Subanesthetic Ketamine Exposure in Pregnant Mice and Their Offspring

TL;DR

This study shows that ketamine exposure during pregnancy affects male and female mouse offspring differently, with males showing reduced depression-like behaviors.

Contribution

The study reveals sex-specific neurobehavioral effects of prenatal ketamine exposure and identifies potential mechanisms involving NMDA receptor subunits.

Findings

Prenatal ketamine reduced depression-like behaviors in male offspring but not in females.

Male offspring had increased dendritic spine density in dentate gyrus granule cells.

Higher levels of GluN2A and GluN3A in male embryos suggest sex-dependent effects of ketamine.

Abstract

Depression during pregnancy is often overlooked and undertreated. Ketamine has been shown to exert prompt and sustained antidepressant effects in patients with depression, although concerns of potential neurotoxicity prohibit its use in pregnant women. Here, we aim to investigate the neurobehavioral effects of subanesthetic ketamine on pregnant mice and their offspring. We found that pregnant C57BL/6 mice receiving ketamine (10 mg/kg/day intraperitoneal) from gestation day 15 to 17 exhibited less depression-like behaviors. Prenatal ketamine treatment induced male-specific reduction in depression- and anxiety-like behaviors in adult offspring, without alterations in social and memory performance. These behavioral outcomes were associated with a male-specific increase in dendritic spine density of dentate gyrus granule cells, while neither dendritic architecture nor hippocampal neurogenesis was affected. N-methyl-D-aspartate receptor subunits GluN2A and GluN3A were expressed at significantly higher levels in the hippocampus of male as compared to female mouse embryos, suggesting sex-dependent actions of ketamine on developing brain. Overall, our study showed that prenatal exposure to subanesthetic ketamine could exert long-lasting neurobehavioral effects in a sex-dependent manner, with male offspring being more resilient to stress. These findings may have implications concerning ketamine use during pregnancy, and also provide clues about the developmental origins of emotional problems.

The online version contains supplementary material available at 10.1007/s10571-025-01582-w.

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