Abstracts

RATIONALE: Synaptic reorgnization after neural injury may form the basis of recurrent excitatory networks in epileptic foci. Axon guidance molecules including the semaphorins (sema) provide targeting information to axons along predetermined pathways during development. Whether these cues underlie the formation of maladaptive circuits during synaptic reorganization and epileptogenesis in the mature brain is unclear. Sema 3C ligand and receptor mRNA content is selectively down-regulated in CA1 pyramidal cells of mature rat hippocampus during the epoch of synaptic reorganization after kainic acid status epilepticus (KA-SE). This suggested the hypothesis that loss of tonic activation of the sema 3C receptor may lead to axonal sprouting from CA1 pyramidal cells. The regulation of sema 3C receptor expression in CA1 of mouse hippocampus after KA-SE has not previously been investigated. METHODS: To determine whether sema 3C expression is altered after KA-SE, in situ hybridization of both NPN1 and NPN2 subunits was performed through hippocampus. Both C57/B6 and FVB strains were studied because the strains exhibit equivalent sensitivity to KA-SE but only FVB mice exhibit death of CA3/hilar neurons and synaptic reorganization (Schauwecker et al, Exp. Neurol 2000). RESULTS: Despite equivalent intensity of behavioral seizures,death of CA3c/hilar neurons was evident in FVB but not C57/B6 mice. Both NPN1 and NPN2 mRNA content in CA1 cell layer in FVB but not C57/B6 mice was decreased by 50% and 40% (p<0.0001) respectively 7 days after KA-SE. CONCLUSIONS: These data demonstrate that status epilepticus is necessary but not sufficient to regulate NPN gene expression. The present findings raise the interesting possibility that decreased sema 3C receptor activation may contribute to CA1 axonal sprouting which may occur only in FVB but not C57/B6 mice, a scenario reminiscent of mossy fiber sprouting in these two strains. Recurrent excitatory synapses among CA1 pyramidal cells may form maladaptive circuits which underlie epileptogenesis in the KA model. Supported by NINDS and Exelixis Pharmaceuticals, Inc.