Astrocyte dysfunction drives abnormal resting-state functional connectivity in depression

Even though brain-wide network-level abnormalities in major depressive disorder (MDD) patients via resting-state functional MRI (rsfMRI) exist, the mechanisms underlying such network changes are unknown. Here, we show that the astrocytic calcium deficient mice, inositol 1,4,5-trisphosphate-type-2 receptor knockout mice (Itpr2-/- mice), display abnormal rsfMRI connectivity (rsFC), which is highly consistent with those of MDD patients. Optogenetic activation of medial prefrontal cortex (mPFC) astrocytes partially rescues rsFC. Optogenetic activation of the mPFC neurons or mPFC-striatum pathway rescues disrupted rsFC and depressive-like behaviors in Itpr2-/- mice. Our results identify the previously unknown role of astrocyte dysfunction in driving rsFC abnormalities in depression.