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7  SUMMARY

In this study, the impact of membrane-associated factors on axonal outgrowth during development and following lesion was examined. We studied the maturation-dependent features of membrane-associated molecules in the hippocampus with the stripe assay for guidance activity and with the outgrowth assay for outgrowth-supporting activity.

We could show that entorhinal axons discriminate between their proper target area, the hippocampus, and control regions which do not receive synaptic connections from the entorhinal cortex, and preferred to grow on hippocampal membranes. Further, we examined guidance preferences of entorhinal neurites on hippocampal membranes in different developmental stages. The choice behavior of entorhinal neurites for hippocampal membranes temporally correlates with the ingrowth of the perforant path into the hippocampus and with the stabilization of this brain area in vivo, and further indicate the transient presence of membrane-associated guidance cues in the hippocampus.

One of the characteristics of maturational processes in the central nervous system is the developmentally regulated myelination of fiber tracts. Comparison of the stripe assay data with immunohistochemical analysis for MBP and MAG as representative myelin markers revealed a correlation between the changes in axonal choice behavior and increasing myelination. It is known that myelin itself is a strong axonal outgrowth inhibitor and that myelin can also induce growth cone collapse. In outgrowth assays, we could show that myelin has a strong outgrowth inhibitory influence on entorhinal axons which can be neutralized by the monoclonal antibody IN-1. However, in the stripe assay, myelin did not influence the choice behavior of outgrowing axons and this indicates that myelin does not govern information for directed growth. Furthermore, stripe assays were performed with membranes obtained from deafferented hippocampi at various lesion stages. In these experiments, we could show that outgrowth-promoting factors are present in the lesioned hippocampus. Moreover, data from the stripe assay revealed the timely restricted presence of membrane-bound guidance factors which are equally as attractive as neonatal hippocampal membranes. These experiments indicate the lesion-induced expression of outgrowth-promoting factors in the hippocampus, which correlates temporally with the sprouting reaction in vivo.

It is suggested that the central nervous system of adult vertebrates is determined in its cellular condition and not capable of structural changes. This is most evident following lesion of adult brain, where the ability for regeneration is highly restricted in comparison to young, postnatal neural tissue. This restricted ability for regeneration in the adult brain is essentially determined by the presence of outgrowth-inhibitory myelin. However, a compensatory [Seite 58↓]sprouting response exists in the adult hippocampus following lesion, which leads to a layer-specific replacement of lost synaptic contacts. The identification of these factors will lead to a deeper understanding of layer-specific axonal sprouting and synaptic replacement. Further, the identification and characterization of the underlying factors will help us to understand the potential and limitations of regeneration in the central nervous system.

Keywords: axon guidance molecule, regeneration, hippocampus, sprouting, IgCAM, Collapse, Attraction, Myelin, outgrowth-promoting molecules.


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