N-methyl-d-aspartate-triggered neuronal death in organotypic hippocampal cultures is endocytic, autophagic and mediated by the c-Jun N-terminal kinase pathway.
Acute excitotoxic neuronal death was studied in rat organotypic hippocampal slices exposed to 100 micro mN-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.
Borsello
Tiziana
T
Institut de Biologie cellulaire et de Morphologie, Université de Lausanne, Rue du Bugnon 9, CH-1005, Switzerland.
Croquelois
Karine
K
Hornung
Jean-Pierre
JP
Clarke
Peter G H
PG
D000818:Animals; D001343:Autophagy / Q000502:physiology*; D016923:Cell Death / Q000502:physiology; D004334:Drug Administration Schedule; D004705:Endocytosis / Q000502:physiology*; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D006735:Horseradish Peroxidase / Q000493:pharmacokinetics; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D016202:N-Methylaspartate / Q000008:administration & dosage / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D018696:Neuroprotective Agents / Q000494:pharmacology; D009924:Organ Culture Techniques; D010544:Peroxidases / Q000493:pharmacokinetics; D010766:Phosphorylation; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D051381:Rats
D018696:Neuroprotective Agents; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D016202:N-Methylaspartate; D006735:Horseradish Peroxidase; D010544:Peroxidases; C021799:microperoxidase; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases