Recombinant Human Thrombospondin-1 Protein Rapidly Relieve Depression in Mice Via Uncoupling the Dopamine D1-D2 Receptor Complex

Deficits in astrocytes function contribute to major depressive disorder (MDD) and suicide, but it remains unclear the therapeutic effect of directly reactivating astrocyte in depression. Here, specific gain and loss of astrocytic cell functions in the medial prefrontal cortex (mPFC) bidirectionally regulates depression-like symptoms. Remarkably, recombinant human Thrombospondin-1 (rhTSP1), an astrocyte-secreted protein, exerted rapidly antidepressant-like actions through mPFC TH/dopamine/D2R pathways, but not D1R. TSP1 in the mPFC might have potential as a target for treating clinical depression.