Implication of microglia in ketamine-induced long-term cognitive impairment in murine pups

Abstract

Background: Ketamine, a non-competitive N-methyl-D-aspartate receptor (NMDAR) antagonist, is widely applicable to anesthesia, analgesia, and sedation. However, the function and mechanisms of ketamine in the long-term learning and memory function of neonatal mice are unclear. Objective: The present study aims to investigate whether long-term learning and memory function will be affected by multiple ketamine exposures in the early development period. Methods: The mRNA and protein levels were measured by RT-qPCR and western blot, respectively. The Morris Water Maze test was performed to assess spatial learning and memory. Results: We identified that neonatal exposure to ketamine downsized the positive neurons for microtubule-associated protein doublecortin (DCX) and Ki67 in hippocampal dentate gyrus at the juvenile and late adolescence stages. Double-labeling tests demonstrated that the counts of Iba1+ cells and Ki67+ cells were pronouncedly diminished with exposure to ketamine. Further, qPCR assays to screen the key factors predisposing the populations and maturation of microglia exhibited remarkable decline of CX3CR1 mRNA levels in ketamine group versus the control group. The close relation of microglia to synaptic plasticity was depicted by the significantly downregulated synaptic plasticity-related proteins NR2B and PSD-95 subsequent to multiple exposures to ketamine. Finally, we found that both the protein and mRNA levels of BDNF were markedly decreased in ketamine group versus the control group. Conclusion: We found that multiple exposures to ketamine in neonatal mice lead to spatial learning and memory dysfunction. The alterations of microglial development and function are the possible mechanisms of long-term learning and memory impairment.