Gene expression profiles in HMC3 cells after exposure to ketamine or its active metabolites: 2R6R-HNK and 2S6S-HNK

This study was designed to clarify mechanisms of action for ketamine and its active metabolites, (2R,6R;2S,6S)-hydroxynorketamine (HNK), which also appear to play a major role in ketamine's rapid antidepressant effects. An HMC3 human microglial cell line was used as a model system to test a possible role for ketamine in immune response regulation that might contribute to its antidepressant effects. Our results highlight the fact that ketamine and its two active metabolites can regulate the type I interferon pathway mediated, at least partially, through STAT3 which plays a major role in the immune response. Specifically, STAT3 downstream genes that were modulated by either ketamine or its active metabolites were enriched in the “response to type I interferon” pathway. Our data also suggest that STAT3 might play a role in ketamine's antidepressant effects, mediated, at least in part, through EEF2, resulting in the augmentation of BDNF expression and promoting the synthesis of synaptic proteins PSD95 and SYN1. Overall design: To determine gene expression profiles in HMC3 cells after exposure to vehicle, Estradiol (E2), ketamine, (2R,6R)-HNK, (2S,6S)-HNK, E2+ketamine, E2+(2R,6R)-HNK, and E2+(2S,6S)-HNK.