Kisspeptin is a C-terminally amidated peptide encoded by the KiSS1 gene. The peptide and its receptor GPR54 are abundant in the hypothalamus and have been implicated as gatekeepers for the onset of puberty and the development of the reproductive system. Interestingly, GPR54 is also highly expressed in granule cells of the hippocampal dentate gyrus, and in a previous study we showed that kisspeptin enhances excitatory synaptic transmission in these cells. The present study examined how expression of KiSS1 and GPR54 is regulated in rat hippocampus, using in vivo and in vitro preparations. In animals, a 3 h period of kainate-induced seizures significantly altered expression of both genes. KiSS1 mRNA showed a 3-4 fold increase which peaked 1-3 days post-seizure and subsided after one week. GPR54 mRNA, on the other hand, was reduced by 20-30% at 6-24 h. In organotypic hippocampal slice cultures, brief exposure to kainate produced a significant increase in KiSS1 mRNA with a time course comparable to that in vivo, and the effect was blocked by tetrodotoxin and CNQX. Chronic (7-day) treatment with picrotoxin, which induced a persistent four-fold increase in spike activity in multi-electrode recordings, caused a similar size but more persistent upregulation in KiSS1 mRNA. As in other studies, kainate and picrotoxin induced an upsurge in BDNF expression, but BDNF mRNA was also significantly increased when slice cultures were treated with kisspeptin. Taken together, KiSS1 expression is upregulated by neuronal activity and activation of GPR54 by kisspeptin may in turn contribute to sustain basal BDNF levels required for hippocampal function. In additional experiments, KiSS1 mRNA was found to be increased after orchidectomy and thus expression may be regulated also by gonadal hormones.