Although we cannot exclude an exogenous role of P2X4R in neurons, we showed for the first time that overexpression of P2X4Rs dramatically suppressed the microglial activation and the mRNA levels of TNF-α and IL-1β in the hippocampus of T2DM rats, indicating that the P2X4R is an upstream signaling molecule in the regulation of microglial activation. This evidence concerns the gene TNF and type 2 diabetes mellitus.