Sex-Specific Alterations in Spatial Memory and Hippocampal AKT-mTOR Signaling in Adult Mice Pre-exposed to Ketamine and/or Psychological Stress During Adolescence

Ketamine is administered to manage major depression in adolescent patients. However, the long-term effects of juvenile ketamine exposure on memory-related tasks have not been thoroughly assessed. We examined whether exposure to ketamine, psychological stress, or both, results in long-lasting alterations in spatial memory in C57BL/6 mice. Furthermore, we evaluated how ketamine and/or psychological-stress history influenced hippocampal protein-kinase b–mammalian target of rapamycin (AKT-mTOR)-related signaling. Male and female postnatal day (PD)-35 mice underwent vicarious defeat stress (VDS), a form of psychological stress that reduces sociability in both sexes, with or without ketamine exposure (20 mg/kg/day; PD35-44). In adulthood (PD70) mice were assessed for spatial memory performance on a water-maze task or euthanized for hippocampal tissue collection. Juvenile pre-exposure to ketamine or VDS, individually, increased the latency (sec) to locate the escape platform in adult male, but not female, mice. However, juvenile history of concomitant ketamine-and-VDS prevented memory impairment. Furthermore, individual ketamine or VDS pre-exposure, unlike their combined history, decreased hippocampal AKT-mTOR-signaling in adult male mice. Conversely, ketamine pre-exposure alone increased AKT-mTOR in the hippocampus of adult female mice. Lastly, rapamycin-induced decreases of mTOR in naïve adult female mice induced spatial-memory retrieval deficits, mimicking adult males with VDS- or ketamine-history. Our preclinical model displays how ketamine treatment, for the management of adolescent psychological stress-induced sequelae, does not impair spatial-memory later in life. However, juvenile recreational ketamine misuse, like psychological stress history, results in long-term spatial memory deficits, along with alterations of hippocampal AKT-mTOR signaling, in a sex-specific manner.