title: Epileptiform activity interferes with proteolytic processing of Reelin required for dentate granule cell positioning.
abstract: 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.
authors.affiliation: Experimental Epilepsy Group, Neurocenter, University Clinic Freiburg, Freiburg, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Tinnes
authors.forename: Michael K E
authors.initials: MK
authors.lastname: Schäfer
authors.forename: Armin
authors.initials: A
authors.lastname: Flubacher
authors.forename: Gert
authors.initials: G
authors.lastname: Münzner
authors.forename: Michael
authors.initials: M
authors.lastname: Frotscher
authors.forename: Carola A
authors.initials: CA
authors.lastname: Haas
mesh_terms: D000818:Animals; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics / Q000378:metabolism*; D018891:Dentate Gyrus / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004827:Epilepsy / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D005109:Extracellular Matrix / Q000378:metabolism / Q000473:pathology; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D018093:Gelatinases / Q000378:metabolism; D015870:Gene Expression / Q000502:physiology; D006056:Golgi Apparatus / Q000378:metabolism; D007395:Interneurons / Q000473:pathology / Q000502:physiology; D007608:Kainic Acid / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009924:Organ Culture Techniques; D010447:Peptide Hydrolases / Q000378:metabolism*; D010455:Peptides; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D000091042:Reelin Protein; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*
chemical_list: D015816:Cell Adhesion Molecules, Neuronal; D018690:Excitatory Amino Acid Agonists; D016326:Extracellular Matrix Proteins; D009419:Nerve Tissue Proteins; D010455:Peptides; D000091042:Reelin Protein; C000717129:Reln protein, rat; C120583:transfecting peptide I; D011189:Potassium Chloride; D010447:Peptide Hydrolases; D012697:Serine Endopeptidases; D018093:Gelatinases; D007608:Kainic Acid