Mossy fiber sprouting (MFS) in the hippocampal dentate gyrus is thought to play a critical role in the hyperexcitability of the hippocampus in temporal lobe epilepsy patients. The composition of molecular signals that is needed to direct this sprouting response has not yet been elucidated to a great extent. In the present study we investigated the expression profile of Sema3A mRNA and the axonal growth-associated protein GAP-43 mRNA during the process of electrically induced epileptogenesis in rats. Sema3A is an axon guidance molecule with repellent activity on dentate granule cell axons. It is produced by neurons in the entorhinal cortex, which synapse on the dendrites of dentate granule cells. Upregulation of GAP-43 expression in granule cells has often been reported in conjunction with MFS. After induction of status epilepticus, the expression of Sema3A mRNA was temporarily downregulated in the entorhinal cortex concomitantly with an upregulation of GAP-43 mRNA in dentate granule cells. In the following days, robust MFS into the dentate molecular layer was observed. When the induction of status epilepticus was incomplete the two responses appeared to dissociate, i.e., the downregulation of Sema3A mRNA did not occur, while upregulation of GAP-43 mRNA in dentate granule cells was still displayed. However, in these rats no significant MFS was observed. These findings indicate that Sema3A mRNA downregulation is temporarily correlated with MFS, while GAP-43 upregulation per se is not, and suggest that a loss of Sema3A in the molecular layer of the dentate gyrus could facilitate MFS into this area during epilepsy. © 2003 Elsevier Science (USA). All rights reserved.