C/EBPβ/AEP pathway mediates synaptic impairments and depression-like phenotypes induced by chronic stress

Depression is a common psychiatric disorder characterized by episodes of low mood. Disruptions in synaptic homeostasis contribute to the onset of depression. However, the molecular mechanisms underlying synaptic impairments in depression remain elusive. Here we show that chronic stress activates the transcription factor CCAAT/enhancer binding protein β (C/EBPβ) and elevates the expression of its downstream protease asparagine endopeptidase (AEP). Knockout of C/EBPβ or AEP alleviates the depression-like phenotypes induced by chronic unpredictable mild stress, whereas overexpression of C/EBPβ or AEP in the hippocampus replicates these phenotypes. Genetic deletion of AEP attenuates the detrimental effect induced by C/EBPβ overexpression. These findings indicate that the C/EBPβ/AEP pathway plays a key role in the pathogenesis of depression.