Mature cerebellar granule cells in culture die by a process that requires new RNA and protein synthesis when deprived of depolarizing concentrations of potassium. We investigated gene expression during the early phase of the cell death program evoked by potassium deprivation. Using a differential gene display technique, we isolated a cDNA that was increased by potassium deprivation. This cDNA was homologous to the 3' mRNA end of neuronal pentraxin 1 (NP1), a gene encoding a secreted glycoprotein whose expression is restricted to the nervous system. Reverse-Northern and Northern blot analyses confirmed that treatment with low potassium induces overexpression of NP1 mRNA, with a subsequent increase in NP1 protein levels. Time-course studies indicated that overexpression of NP1 protein reaches a maximum after 4 h of exposure to potassium deprivation and 4 h before significant cell death. Incubation of cerebellar granule cells with an antisense oligodeoxyribonucleotide directed against NP1 mRNA reduced low potassium-evoked NP1 protein levels by 60% and attenuated neuronal death by 50%, whereas incubation with the corresponding sense oligodeoxyribonucleotide was ineffective. Furthermore, acute treatment with lithium significantly inhibited both overexpression of NP1 and cell death evoked by low potassium. These results indicate that NP1 is part of the gene expression program of apoptotic cell death activated by nondepolarizing culture conditions in cerebellar granule cells.