Together with the functional and behavioral data, our molecular and morphological studies provide evidence to prove the fact that hippocampal PRG-1 drives a cell-autonomous signaling pathway involved in the regulation of spine density, and subsequently pain and depression-like behavior control via P2X7R/PRG-1/PP2A pathway, thus providing theoretical basis for a novel analgesia and depression relief strategies targeting PRG-1. The gene discussed is PTPA; the disease is depressive disorder.