Deficiency of astrocyte CysLT₁R ameliorates depression-like behaviors in mice by modulating glutamate synaptic...

Our previous study suggests that hippocampal cysteinyl leukotriene receptor 1 (CysLT₁R) could be involved in depression. Herein we hypothesize that CysLT₁R may regulate depression by affecting synaptic glutamate cycling based on existence of CysLT₁R in the astrocytes that participate in occurrence of depression. We found that CysLT₁R expression was significantly increased in the astrocyte of chronic unpredictable mild stress (CUMS)-induced depression-like mice, CysLT₁R astrocyte-specific conditional knockout (AcKO) significantly improved depression-like behaviors, as indicated by decreased immobility time in the forced swimming test and tail suspension test and increased sucrose preference in the sucrose preference test, and knockdown of CysLT₁R in the astrocyte of dentate gyrus (DG), the region with the most significant increase of CysLT₁R in the astrocyte of depression-like mice, produced similar effects. Correspondingly, overexpression of CysLT₁R in the astrocyte of DG induced depression-like behaviors in mice. The further study showed that CysLT₁R AcKO ameliorated synaptic plasticity impairment, as reflected by increased synapse, LTP and PSD95, and promoted glutamate transporter 1 (GLT-1) expression by inhibiting NF-κB p65 nuclear translocation mediated by β-arestin2 and clatrhin, subsequently decreased glutamate in synaptic cleft and GluN2B on postsynaptic membrane in depression-like mice. The present study also showed that GLT-1 agonist or NF-κB inhibitor ameliorated depressive-like behaviors induced by overexpression of the astrocyte CysLT₁R of DG. Our study demonstrated that astrocyte CysLT₁R regulated depression by modulating glutamate synaptic transmission, suggesting that CysLT₁R could be a potential target for developing novel drugs of anti-depression.