We have localized brain-derived neurotrophic factor (BDNF) mRNA in rat brain and examined its regulation by seizure activity. In situ hybridization of BDNF 35S-cRNA most prominently labeled neurons in hippocampal stratum pyramidale and stratum granulosum, superficial olfactory cortex, pyramidal cell layers of neocortex, amygdala, claustrum, endopiriform nucleus, anterior olfactory nucleus, and ventromedial hypothalamus. Hybridization to BDNF mRNA was markedly increased in all of these regions after lesion-induced recurrent limbic seizures and within dentate gyrus granule cells following one electrically stimulated epileptiform afterdischarge. In contrast to seizure-elicited changes in nerve growth factor (NGF) mRNA expression, increases in BDNF mRNA occur in a greater number of different neuronal populations and develop several hours more rapidly in extrahippocampal loci. These results indicate that regulation by physiological activity may be an intrinsic property of this class of neurotrophic factor but that, in the recurrent seizure paradigm, different mechanisms mediate increased expression of mRNAs for BDNF and NGF outside hippocampus.