ABSTRACT
The host response to neural injury, which can include axonal sprouting and synaptic reorganization is likely to be under tight genetic regulatory control at the level of the genome and may be implicated in epileptogenesis. Despite its importance, however, the molecular basis of synaptic reorganization is unclear. We have studied the development of synaptic reorganization, semaphorin gene expression, and epileptogenesis in hippocampus of epileptogenic sensitive (FVB/NJ) and epileptogenic resistant (C57BL/6J) mice (i.e. distinct genetic backgrounds) after kainic acid-induced status epilepticus. Our results support the hypothesis that disruption of transcriptional regulation of axon guidance genes leads to a differential loss of tonic neuropilin-2 dependent activation of semaphorin 3F receptors on hippocampal neurons on distinct genetic backgrounds. This results in rearranged synaptic circuitry and thus promotes epileptogenesis. These findings may define biologic principles underlying the role of semaphorin signaling which may broadly apply to other systems undergoing neural regeneration.
Subject(s)
Brain Chemistry/genetics , Excitatory Amino Acid Agonists , Gene Expression Regulation/physiology , Kainic Acid , Semaphorins/biosynthesis , Status Epilepticus/metabolism , Animals , Axons/metabolism , Blotting, Northern , Cell Count , Cloning, Molecular , Dentate Gyrus/metabolism , Deoxyglucose/metabolism , GAP-43 Protein/metabolism , Immunoblotting , Immunohistochemistry , In Situ Hybridization , Male , Mice , Mice, Inbred C57BL , Mice, Inbred Strains , Pyramidal Tracts/metabolism , RNA Probes , Semaphorins/genetics , Species Specificity , Status Epilepticus/chemically induced , Status Epilepticus/genetics , Synapses/physiologyABSTRACT
A small injection of wheat germ agglutinin conjugated to horseradish peroxidase (WGA-HRP) was injected into dorsal or ventral peripheral retina in normal goldfish and in goldfish with prior optic nerve crush. Serial sections of tectum were subsequently taken for horseradish peroxidase (HRP) histochemistry 18 hours after injection and studied with light microscopy and densitometric reconstructions. In normals, a small, sharply delineated patch of product 200-300 microns wide was observed at the appropriate medial or lateral periphery of tectum. This product filled the entire SFGS, the main optic termination layer, and fell off abruptly at its edges. No labelling was detected in the optic pathways. In regenerates at about 20 days after nerve crush, these retinal injections yielded product that was dispersed across 1,000 microns or more of tectum but not in a uniform fashion. The densest product was biased toward the appropriate tectal position while product of intermediate density was mainly distributed along a path from the anterior end of tectum to this region. Product in the inappropriate half of tectum was much lighter and typically fiberlike in appearance. By about 40 days, product had condensed considerably at roughly the correct region of tectum but it was not as sharply delimited as in normals. Dense label occupied a single area about twice that of normals and exhibited flanking regions of light label extending for several hundred micrometers. At 59-148 days, a further condensation was observed but into more than one patch of product. The patches were of variable size and consisted of sharply delimited dense product which filled the entire SFGS at each position. Morphologically, these patches bore a remarkable resemblance to the ocular dominance columns previously seen in this system.
