Nedd4l downregulation of NRG1 in the mPFC induces depression-like behaviour in CSDS mice

The occurrence of major depressive disorders has been closely related to the vulnerability of stress. The medial prefrontal cortex (mPFC) is involved in regulating pathological reactivity to stress, changes in affective behaviour and cognitive functions by distress. Increasing evidence indicates that neuregulin 1 (NRG1) plays an important role in psychiatric illnesses, including depression, schizophrenia and bipolar disorder. However, whether NRG1 in the mPFC is related to stress vulnerability remains unclear. We here assessed the regulation of NRG1 by the E3 ubiquitin ligase Nedd4l (neural precursor cell expressed developmentally downregulated 4-like) and investigated whether NRG1 changes in the mPFC might lead to vulnerability to depression-like behaviours. We've identified a deficiency of NRG1 in the mPFC as a key factor that contributes to the regulation of stress susceptibility in mice, as further suggested by the finding that overexpression of NRG1 attenuated depression-like behaviours in the animal model of chronic social defeat stress (CSDS). Interestingly, RNA sequencing in the mPFC brain region showed no differences in NRG1 mRNA levels between control animals and stress-susceptible (SS) or resilient mice (RES) following CSDS. However, mRNA and protein levels of Nedd4l were markedly increased in SS mice, but not in RES mice compared to controls. Furthermore, ubiquitination of NRG1 was increased in SS mice. Remarkably, overexpression of Nedd4l in mouse mPFC induced a decrease in NRG1 level and caused vulnerability to stress by subthreshold social defeat stress (SSDS), while downregulation of Nedd4l expression in the mPFC rescued the vulnerability to stress-induced social avoidance and anhedonia. Our data strongly indicate that the Nedd4l-mediated downregulation of NRG1 acts as a critical role in depression-like phenotypes of mice in CSDS.