In this study, we provide evidence for direct modulatory effects of the chemokine, CXCL10, on the physiology of hippocampal neurons maintained in primary culture. CXCL10 elicited a rise in intracellular Ca2+ and enhanced both spontaneous and evoked electrical activity of hippocampal neurons. CXCL10-induced elevations in intracellular Ca2+ were associated with an increase in neuronal firing and an alteration in the relationship between the evoked Ca2+ signal and neuronal activity. The effects of CXCL10 were not accompanied by a shift in resting membrane potential (RMP) or input resistance. Expression of the CXCR3 chemokine receptor supports a direct effect of CXCL10 on hippocampal neurons.