Ketamine alleviates fear memory and spatial cognition deficits in PTSD rat model via BDNF signaling pathway of hippocampus and amygdala

Post-traumatic stress disorder (PTSD) is associated with traumatic stress experiences. This condition can be accompanied by learning and cognitive deficits, contributing to increased rates of disability in people with PTSD. Studies have shown that that ketamine can rapidly and significantly alleviate symptoms in patients with chronic PTSD. Nevertheless, the effects of ketamine on neurocognitive impairment and its mechanism of action in PTSD remain unclear. In this study, the gradient dose-related effects of ketamine (5, 10, 15, and 20 mg/kg, i.p.) on spatial and fear memory were evaluated in a rat model of single prolonged stress and electric foot shock (SPS&S). Expression levels of brain-derived neurotrophic factor (BDNF) and post-synaptic density-95 (PSD-95) in the hippocampus (HIP) and amygdala (AMG) were determined by Western blot analysis, immunohistochemistry, and quantitative real-time PCR assays. The data showed that rats subjected to SPS&S exhibited significant PTSD-like cognitive impairment.The effect of ketamine on SPS&S-induced neurocognitive function showed a U-shaped dose effect in rats. A single administration of ketamine at a dosage of 10 ~ 15mg/kg resulted in significant changes in behavioral outcomes. And these improvements in cognitive function and molecular changes were reversed at high doses (15 ~ 20mg/kg). Overall, Ketamine reversed SPS&S-induced fearand spatial memory impairment and down-regulation of BDNF and BDNF-related PSD-95 signaling in the HIP and AMG. And the dose of 15 mg/kg reversed behavioral and molecular changes rapidly, and promoted the amelioration of cognitive dysfunction. The enhanced association of BDNF signaling with PSD-95 influences could participate in the therapeutic efficiency of ketamine for PTSD.