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). The gene discussed is SLC12A5; the disease is depressive disorder.