Ketamine alleviates PTSD-like effect and improves hippocampal synaptic plasticity via regulation of GSK-3ß/GR signaling of rats.

ABSTRACT

BACKGROUND: Each year, 3-4% of the global population experiences post-traumatic stress disorder (PTSD), a chronic mental disorder with significant social and economic repercussions. Although it has been shown that ketamine can effectively alleviate PTSD symptoms in individuals, the specific mechanism of action underlying its anti-PTSD effects remains unclear. In this study, we investigated how a single, low dose of ketamine affected the glycogen synthase kinase 3ß (GSK-3ß)/glucocorticoid receptor (GR) signaling pathway in a single prolonged stress (SPS)-induced PTSD rat model. METHODS: After establishing the model, stress-related behavioral alterations in the rats were assessed following intraperitoneal injections of ketamine (10 mg/kg) and GSK-3ß antagonist SB216763 (5 mg/kg). In the hippocampus, alterations in the expression of specific proteins implicated in PTSD development, such as GR, brain-derived neurotrophic factor (BDNF), GSK-3ß, and phosphorylated glycogen synthase kinase 3ß (p-GSK-3ß), were assessed. We also measured changes in the mRNA expression levels of GR, BDNF, GSK-3ß, FK501 binding protein 51 (FKBP5), and corticotropin-releasing hormone (CRH), as well as synaptic ultrastructure, in the hippocampus, and measured changes in corticosterone levels in the blood. RESULTS: SPS induced anxiety-like and depression-like behaviors in rats and induced morphological changes in synapse, which were accompanied by higher GSK-3ß protein expression and conversely, decreased expression of GR, BDNF, p-GSK-3ß, FKBP5 and CRH. Intraperitoneal administration of ketamine (10 mg/kg) after SPS prevented SPS-induced anxiety-like behaviors. Most importantly, ketamine attenuated SPS-induced dysfunctions in GSK-3ß/GR signaling and synaptic deficits. Furthermore, treatment with a GSK-3ß inhibitor played the same effect as ketamine on behavioral changes of SPS model rats. CONCLUSION: Single doses of ketamine effectively ameliorate SPS-induced anxiety-like symptoms, potentially by improving synaptic plastic in the hippocampus by regulating GSK-3ß/GR signaling.