Abstracts

Synaptic reorganization after neural injury may form the basis of recurrent excitatory networks and the development of spontaneous recurrent seizures. Axon guidance cues including the semaphorins may participate in this process of synaptic reorganization. Mouse models where one population of animals (FVB/N mice) develops permanent morbidity (i.e epilepsy) in response to neural injury (Kainic acid status epilepticus, KA-SE) with another population of animals (C57Bl/6 mice) resistant to the long term effects of KA-SE would facilitate the identification of candidate axon guidance genes involved in synaptic reorganization and epileptogenesis. FVB/N (seizure sensitive) but not C57Bl/6 mice (seizure resistant) have KA-SE induced cell death of CA3/Hilar neurons, decreased hippocampal gene expression of Semaphorin 3F ligand and receptor (Neuropilin 2) systems, axonal sprouting of hippocampal neurons, and epilepsy. These data prompt the hypothesis that transcriptional regulatory complexes unique to the hippocampal neurons of FVB/N but not C57Bl/6 mice may define its susceptibility to KA-SE induced neural injury, synaptic reorganization, and subsequent epileptogenesis.
To determine if genetic expression of transcriptional factors and regulatory signaling pathways in these mice are altered after KA-SE, we have used microarray technology to evaluate the content of the transcriptome in mouse hippocampus after kainic acid induced status epilepticus.
The data suggest that a unique set of genes is regulated in hippocampal neurons from FVB/N mice (i.e. those animals with KA induced cell death and epileptic circuitry) but not in C57Bl/6 mice after KA-SE. Regulation of semaphorin gene transcription may be due to activation of either cAMP or MAP protein kinase pathways in KA sensitive hippocampal neurons. The targets of these signaling cascades may include the transcriptional regulatory proteins elk3/Net, REST/NRSF, and Sin3B. Interestingly, only the class III semaphorin ligand and receptor gene families are regulated at the transcriptional and protein level in hippocampus from FVB/N (seizure sensitive strain) but not C57Bl/6 mice (seizure resistant strain) after KA-SE. Further experiments using a novel adult mouse hippocampal slice culture system and proteomics to investigate the putative functional roles of identified proteins in the regulation of class III semaphorin gene expression will be reported.
The data suggest that a distinct set of signaling cascades, transcriptional regulatory factors, and target genes of the class III semaphorin gene family may play a pivotal role in synaptic reorganization and epileptogenesis. These findings may define biologic principles governing the use of semaphorin signaling which may broadly apply to other systems undergoing neural regeneration.
[Supported by: NINDS, AES, and Kentucky Spinal Cord and Brain Injury Research Trust.]