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N ‐methyl‐ d ‐aspartate‐triggered neuronal death in organotypic hippocampal cultures is endocytic, autophagic and mediated by the c‐Jun N‐terminal kinase pathway
Author(s) -
Borsello Tiziana,
Croquelois Karine,
Hornung JeanPierre,
Clarke Peter G. H.
Publication year - 2003
Publication title -
european journal of neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.346
H-Index - 206
eISSN - 1460-9568
pISSN - 0953-816X
DOI - 10.1046/j.1460-9568.2003.02757.x
Subject(s) - endocytic cycle , microbiology and biotechnology , hippocampal formation , autophagy , chemistry , c jun , terminal (telecommunication) , neuroscience , biology , apoptosis , computer network , receptor , biochemistry , gene , endocytosis , computer science , transcription factor
Acute excitotoxic neuronal death was studied in rat organotypic hippocampal slices exposed to 100 µ m N ‐methyl‐ d ‐aspartate. Fulgurant death of pyramidal neurons occurred in the CA1 and CA3 regions and was already detectable within 2 h of the N‐methyl‐ d ‐aspartate administration. Morphologically, the neuronal death was neither apoptotic nor necrotic but had the hallmarks of autophagic neuronal death, as shown by acid phosphatase histochemistry in both CA1 and CA3 and by electron microscopy in CA1. The dying neurons also manifested strong endocytosis of horseradish peroxidase or microperoxidase, occurring probably by a fluid phase mechanism, and followed, surprisingly, by nuclear entry. In addition to these autophagic and endocytic characteristics, there were indications that the c‐Jun N‐terminal kinase pathway was activated. Its target c‐Jun was selectively phosphorylated in CA1, CA3 and the dentate gyrus and c‐Fos, the transcription of which is under the positive control of c‐Jun N‐terminal kinase target Elk1, was selectively up‐regulated in CA1 and CA3. All these effects, the neuronal death itself and the associated autophagy and endocytosis, were totally prevented by a cell‐permeable inhibitor of the interaction between c‐Jun N‐terminal kinase and certain of its targets. These results show that pyramidal neurons undergoing excitotoxic death in this situation are autophagic and endocytic and that both the cell death and the associated autophagy and endocytosis are under the control of the c‐Jun N‐terminal kinase pathway.