Abstract
In this study, we investigated the hypothesis whether neurotrophins have a differential influence on neurite growth from the entorhinal cortex depending on the presence or absence of hippocampal target tissue. We investigated organotypic brain slices derived from the entorhinal-hippocampal system to analyze the effects of endogenous and recombinant neurotrophin-3 (NT-3) and neurotrophin-4 (NT-4) on neurite outgrowth and reinnervation. In the reinnervation assay, entorhinal cortex explants of transgenic mice expressing enhanced green fluorescent protein (EGFP) were co-cultured with wild-type hippocampi under the influence of recombinant NT-3 and NT-4 (500 ng/ml). Both recombinant NT-3 and NT-4 significantly increased the growth of EGFP+ nerve fibers into the target tissue. Consistently, reinnervation of the hippocampi of NT-4−/− and NT-3+/−NT-4−/− mice was substantially reduced. In contrast, the outgrowth assay did not exhibit reduction in axon outgrowth of NT-4−/− or NT-3+/−NT-4−/− cortex explants, while the application of recombinant NT-3 (500 ng/ml) induced a significant increase in the neurite extension of cortex explants. Recombinant NT-4 had no effect. In summary, only recombinant NT-3 stimulates axon outgrowth from cortex explants, while both endogenous and recombinant NT-3 and NT-4 synergistically promote reinnervation of the denervated hippocampus. These results suggest that endogenous and exogenous NT-3 and NT-4 differentially influence neurite growth depending on the presence or absence of target tissue.
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Acknowledgments
This study was supported in part by grants of the Deutsche Forschungsgemeinschaft to DH (GRK1258) and SH (SPP1394), by a grants from the Berlin-Brandenburg Center for Regenerative Therapies to SH and RN, and by the Investitionsbank Berlin to SH. The authors thank Ari Liebkowsky for editing the manuscript and Sabine Lewandowski for excellent help with the digital image processing.
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The authors D. Hechler and F. Boato contributed equally to this study.
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Hechler, D., Boato, F., Nitsch, R. et al. Differential regulation of axon outgrowth and reinnervation by neurotrophin-3 and neurotrophin-4 in the hippocampal formation. Exp Brain Res 205, 215–221 (2010). https://doi.org/10.1007/s00221-010-2355-7
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DOI: https://doi.org/10.1007/s00221-010-2355-7