Fluoxetine improved depression-like behaviors of PSD mice and upregulated the expression of BDNF in the hippocampus but depletion of BDNF suppressed the effect of fluoxetine. FLX treatment also disassociated the MeCP2-CREB-Bdnf promoter IV complex via phosphorylation of MeCP2 at Ser421 by PKA. This evidence concerns the gene BDNF and major depressive disorder.