Epileptiform activity interferes with proteolytic processing of Reelin required for dentate granule cell positioning
| Autor: | Gert Münzner, Michael Frotscher, Armin Flubacher, Michael K. E. Schäfer, Carola A. Haas, Stefanie Tinnes |
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| Rok vydání: | 2010 |
| Předmět: |
Cell Adhesion Molecules
Neuronal Gene Expression Golgi Apparatus Hippocampus Nerve Tissue Proteins Endoplasmic Reticulum Biochemistry Potassium Chloride Organ Culture Techniques Reeler Interneurons Excitatory Amino Acid Agonists Genetics medicine Animals Secretion Reelin Molecular Biology Secretory pathway Extracellular Matrix Proteins Epilepsy Kainic Acid biology Chemistry Dentate gyrus Serine Endopeptidases Granule cell Extracellular Matrix Rats Granule cell dispersion Cell biology Reelin Protein medicine.anatomical_structure nervous system Gelatinases Dentate Gyrus biology.protein Peptides Peptide Hydrolases Biotechnology |
| Zdroj: | The FASEB Journal. 25:1002-1013 |
| ISSN: | 1530-6860 0892-6638 |
| DOI: | 10.1096/fj.10-168294 |
| Popis: | The extracellular matrix protein Reelin is an essential regulator of neuronal migration and lamination in the developing and mature brain. Lack of Reelin causes severe disturbances in cerebral layering, such as the reeler phenotype and granule cell dispersion in temporal lobe epilepsy. Reelin is synthesized and secreted by Cajal-Retzius cells and GABAergic interneurons, and its function depends on proteolytic cleavage after secretion. The mechanisms regulating these processes are largely unknown. Here, we used rat hippocampal slice cultures to investigate the effect of neuronal activation and hyperexcitation on Reelin synthesis, secretion, and proteolytic processing. We show that enhanced neuronal activity does not modulate Reelin synthesis or secretion. Moreover, we found that intracellular Reelin resides predominantly in the endoplasmic reticulum before it is constitutively secreted via the early secretory pathway. Epileptiform activity, however, impairs the proteolytic processing of Reelin and leads to accumulation of Reelin in the extracellular matrix. We found that both conditions, epileptiform activity and impaired proteolytic cleavage of Reelin, cause granule cell dispersion via inhibition of metalloproteinases. Taken together, our results strongly suggest that secretion of Reelin is activity-independent and that proteolytic processing of Reelin is required for the maintenance of granule cell lamination in the dentate gyrus. |
| Databáze: | OpenAIRE |
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