Epileptiform activity interferes with proteolytic processing of Reelin required for dentate granule cell positioning.
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Epileptiform activity interferes with proteolytic processing of Reelin required for dentate granule cell positioning. / Tinnes, Stefanie; Schäfer, Michael K E; Flubacher, Armin; Münzner, Gert; Frotscher, Michael; Haas, Carola A.
in: FASEB J, Jahrgang 25, Nr. 3, 3, 2011, S. 1002-1013.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - Epileptiform activity interferes with proteolytic processing of Reelin required for dentate granule cell positioning.
AU - Tinnes, Stefanie
AU - Schäfer, Michael K E
AU - Flubacher, Armin
AU - Münzner, Gert
AU - Frotscher, Michael
AU - Haas, Carola A
PY - 2011
Y1 - 2011
N2 - 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.
AB - 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.
KW - Animals
KW - Rats
KW - Extracellular Matrix metabolism
KW - Endoplasmic Reticulum metabolism
KW - Excitatory Amino Acid Agonists pharmacology
KW - Kainic Acid pharmacology
KW - Organ Culture Techniques
KW - Cell Adhesion Molecules, Neuronal genetics
KW - Extracellular Matrix Proteins genetics
KW - Nerve Tissue Proteins genetics
KW - Serine Endopeptidases genetics
KW - Dentate Gyrus metabolism
KW - Epilepsy metabolism
KW - Gelatinases metabolism
KW - Gene Expression physiology
KW - Golgi Apparatus metabolism
KW - Interneurons pathology
KW - Peptide Hydrolases metabolism
KW - Peptides
KW - Potassium Chloride pharmacology
KW - Animals
KW - Rats
KW - Extracellular Matrix metabolism
KW - Endoplasmic Reticulum metabolism
KW - Excitatory Amino Acid Agonists pharmacology
KW - Kainic Acid pharmacology
KW - Organ Culture Techniques
KW - Cell Adhesion Molecules, Neuronal genetics
KW - Extracellular Matrix Proteins genetics
KW - Nerve Tissue Proteins genetics
KW - Serine Endopeptidases genetics
KW - Dentate Gyrus metabolism
KW - Epilepsy metabolism
KW - Gelatinases metabolism
KW - Gene Expression physiology
KW - Golgi Apparatus metabolism
KW - Interneurons pathology
KW - Peptide Hydrolases metabolism
KW - Peptides
KW - Potassium Chloride pharmacology
M3 - SCORING: Journal article
VL - 25
SP - 1002
EP - 1013
JO - FASEB J
JF - FASEB J
SN - 0892-6638
IS - 3
M1 - 3
ER -
