By leveraging ApoE knockout (ApoE−/−) and knockdown (ApoE-KD) mouse models, we demonstrated that ApoE deficiency induced depression-like behaviors, which were closely associated with impaired GABAergic synaptic transmission and down-regulation of ApoE receptors and K+–Cl− cotransporter 2 (KCC2). This evidence concerns the gene SLC12A5 and major depressive disorder.