Genetic dissection of the signals that induce synaptic reorganization

Synaptic reorganization of mossy fibers following kainic acid (KA) administ ration has been reported to contribute to the formation of recurrent excita tory circuits, resulting in an epileptogenic state. It is unclear, however, whether KA-induced mossy fiber sprouting results from neuronal cell loss o r the seizure activity that KA induces. We have recently demonstrated that certain strains of mice are resistant to excitotoxic cell death, yet exhibi t seizure activity similar to what has been observed in rodents susceptible to Kk The present study takes advantage of these strain differences to exp lore the roles of seizure activity vs cell loss in triggering mossy fiber s prouting. In order to understand the relationships between gene induction, cell death, and the sprouting response, we assessed the regulation of two m olecules associated with the sprouting response, c-fos and GAP-43, in mice resistant (C57BL/6) and susceptible (FVB/N) to KA-induced cell death. Follo wing administration of KA, increases in c-fos immunoreactivity were observe d in both strains, although prolonged induction of c-fos was present only i n the hippocampal neurons of FVB/N mice. Mossy fiber sprouting following KA administration was also only observed in FVB/N mice, while induction of GA P-43, a marker associated with mossy fiber sprouting, was not observed in e ither strain. These results indicate that: (i) KA-induced seizure activity alone is insufficient to induce mossy fiber sprouting; (ii) mossy fiber spr outing may be due to the loss of hilar neurons following kainate administra tion; and (iii) induction of GAP-43 is not a necessary component of the spr outing response that occurs following KA in mice. (C) 2000 Academic Press.