Astrocytes mGluR3 deficiency and inhibition restores depressive-like behaviors in CSDS mice

The involvement of metabotropic glutamate receptors (mGluR) in mood regulation has been widely acknowledged. However, the specific changes in the distribution and function of these receptors in astrocytes within mood-related brain regions during depression remain unclear. In this study, we conducted an analysis of astrocytes isolated from mood-related brain regions (mPFC, hippocampus, amygdala, NAc, BNST, and VTA) in CSDS mice to investigate the expression of mGluR3 and mGluR5. Surprisingly, we observed an upregulation of mGluR3 specifically in astrocytes from the mPFC, BNST, and VTA, but not in isolated neurons or microglia. Additionally, we observed an increase in astrocyte reactivation and the release of gliotransmitters (such as glutamate, D-serine, and GABA), while neuronal activities (represented by the frequency and amplitude of sEPSC) were inhibited. Furthermore, we found that by knocking out Grm3 and inhibiting mGluR3 through NAM treatment prior to CSDS, depressive-like behaviors were improved in mice. These findings contribute to a better understanding of the underlying mechanisms of depression and offer new perspectives for the development of antidepressant treatments.