Targeting ApoE–KCC2 Signaling Rescues GABAergic Synaptic Dysfunction and Depression-like Behaviors in Mice

Apolipoprotein E (ApoE) has been implicated in neurodegenerative diseases; however, its function and underlying mechanisms in depression remain elusive. In this study, we employed chronic social defeat stress (CSDS) to establish a mouse model of depression and observed significantly reduced ApoE expression in the hippocampus. By leveraging ApoE knockout (<i>ApoE^-/-</i> ) 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). In addition, we found an interaction between KCC2 and the ApoE receptor low-density lipoprotein receptor (LDLR) through coimmunoprecipitation analysis. Moreover, overexpression of ApoE or targeted activation of GABAergic neurons in the hippocampus significantly reversed depression-like behaviors in both CSDS-exposed and ApoE-KD mice. Lastly, treatment with KCC2 activators, CLP290 and CLP257, restored the expression levels of KCC2 and the GABA_AR α1 subunit, significantly alleviating depression-like behaviors induced by CSDS or ApoE-KD. Together, our results elucidate the pivotal role of ApoE in the pathophysiology of depression and highlight the ApoE-KCC2 signaling pathway as a potential target for developing innovative antidepressant therapies.