p75NTR mediated chronic restraint stress-induced depression-like behaviors in mice via hippocampal mTOR pathway.

AIMS

Major depressive disorder (MDD) is an enduring and severe mood disorder. Previous studies have indicated that p75NTR is involved in neuronal survival and death. However, the specific mechanism of p75NTR in depression remains unknown. The present study aimed to explore the role and mechanism of p75NTR in depression, and try to provide a new target for the treatment of MDD.

MAIN METHODS

The p75NTR knockout and overexpression mice were used to establish a mouse model of depression induced by chronic restraint stress (CRS), and the behavioral effects and potential mechanisms associated with p75NTR knockout/overexpression on CRS-induced depressive mice were investigated by animal behavior, histopathology, immunofluorescence and western blot, respectively.

KEY FINDINGS

The results demonstrate that p75NTR knockout/overexpression can ameliorate the depressive-like behaviors observed in CRS-induced depressive mice. Furthermore, p75NTR knockout/overexpression safeguards the tissue morphology of the hippocampus, inhibits the mTOR signaling pathway to restore autophagy, and modulates apoptosis-related proteins (Bcl-2 and Bax) to reestablish normal levels of autophagy and apoptosis in hippocampal neurons of depressed mice. Importantly, p75NTR knockout/overexpression can improve synaptic plasticity through protecting the dendritic structure and dendritic spines of hippocampal neurons, and upregulating the expression of hippocampal synaptic-related proteins (PSD95 and SYN1).

SIGNIFICANCE

These findings suggest that p75NTR knockout/overexpression can alleviate CRS-induced depression-like behaviors by reinstating autophagy and suppressing apoptosis in hippocampal neurons, and enhancing hippocampal synaptic plasticity via mTOR pathway. These insights may provide potential targets for clinical treatment of depression.