Aberrant sprouting of granule cell axons (mossy fiber) is observed in the dentate gyrus of many patients with temporal lobe epilepsy and in different laboratory animal models of epilepsy. To elucidate the molecular mechanism underlying mossy fiber sprouting in the epileptic hippocampus, we screened activity-regulated genes in the hippocampus, and found that neuritin (also known as candidate plasticity gene 15) expression was rapidly up-regulated after electroconvulsive seizures. Neuritin has also been shown to be inducible in the hippocampus by kainic acid treatment. Overexpression of neuritin increased the number and total length of axonal branches in the cultured granule cells and in the granule cells in organotypic hippocampal slice culture. Kainic acid-dependent axonal branch formation was abolished in the granule cells from neuritin knock-out mice. Molecular mechanisms of neuritin for axonal branch formation was analyzed, and we found that neuritin interact with FGF receptor. Administration of FGF receptor inhibitor prevented neuritin-mediated axonal branch formation in granule cells. FGFs have been shown to induce axonal branches. The cultured granule cells showed FGF-dependent axonal branching. These results suggest that neuritin induction by epileptic seizures triggers aberrant axonal sprouting in the dentate granule cells by activating FGF signal cascade.