Microglial activation is an integral part of neuroinflammation associated with many neurodegenerative conditions. Interestingly, a number of neurodegenerative conditions exhibit enhanced P2X7 receptor (P2X 7R) expression in the neuroinflammatory foci where activated microglia are a coexisting feature. Whether P2X7R overexpression is driving microglial activation or, conversely, P2X7R overexpression is a consequence of microglial activation is not known. We report that overexpression alone of a purinergic P2X7R, in the absence of pathological insults, is sufficient to drive the activation and proliferation of microglia in rat primary hippocampal cultures. The trophic responses observed in microglia were found to be P2X7R specific as the P2X7R antagonist, oxidized ATP (oxATP), was effective in markedly attenuating microgliosis. oxATP treatment of primary hippocampal cultures expressing exogenous P2X7Rs resulted in a significant decrease in the number of activated microglia. P2X7R is unusual in exhibiting two conductance states, a cation channel and a plasma membrane pore, and there are no pharmacological agents capable of cleanly discriminating between these two states. We used a point mutant of P2X7R (P2X7RG345Y) with intact channel function but ablated pore-forming capacity to establish that the trophic effects of increased P2X7R expression are exclusively mediated by the pore conductance. Collectively, and contrary to previous reports describing P2X7R as a "death receptor," we provide evidence for a novel trophic role for P2X7R pore in microglia.