Excitotoxicity by which excitatory amino acid induces neuronal cell death may underlie mechanisms of neurodegenerative diseases. We previously found that c-fos is critically involved in neuronal excitability and survival. Mice that carry hippocampal mutations of c-fos exhibited hyper-excitability, hyper-excitotoxicity and higher mortality in kainic acid (KA)-induced seizures compared to wild-type mice. To further understand the neuroprotective signal transduction pathways regulated by c-fos in the hippocampal formation, we identified 172 genes that are either regulated by KA or are differentially expressed in wild-type and hippocampal-specific c-fos mutant mice using cDNA microarrays. One gene encodes the neuropeptide Y (NPY). We confirmed that c-fos regulates the expression of NPY by using immunohistochemistry. We found that c-fos is critical in up-regulation of NPY expression in the granule cell layer of dentate gyrus in response to KA administration. As NPY is an important endogenous anti-epileptic agent, our result is consistent with a hypothesis that the neuroprotective function of c-fos is mediated in part by regulation of NPY expression. © 2004 Elsevier Ireland Ltd. All rights reserved.