N-methyl-D-aspartate-triggered neuronal death in organotypic hippocampal cultures is endocytic, autophagic and mediated by the c-Jun N-terminal kinase pathway

Tiziana Borsello, Karine Croquelois, Jean Pierre Hornung, P. G H Clarke

Research output: Contribution to journalArticle

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Abstract

Acute excitotoxic neuronal death was studied in rat organotypic hippocampal slices exposed to 100 μM 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.

Original languageEnglish
Pages (from-to)473-485
Number of pages13
JournalEuropean Journal of Neuroscience
Volume18
Issue number3
DOIs
Publication statusPublished - Aug 2003

Fingerprint

JNK Mitogen-Activated Protein Kinases
N-Methylaspartate
Endocytosis
Pyramidal Cells
Autophagy
Dentate Gyrus
Horseradish Peroxidase
Acid Phosphatase
Electron Microscopy
Cell Death
Neurons

Keywords

  • Autophagic cell death
  • Excitotoxicity
  • Neuroprotection
  • Peptide inhibitor
  • Rat

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

N-methyl-D-aspartate-triggered neuronal death in organotypic hippocampal cultures is endocytic, autophagic and mediated by the c-Jun N-terminal kinase pathway. / Borsello, Tiziana; Croquelois, Karine; Hornung, Jean Pierre; Clarke, P. G H.

In: European Journal of Neuroscience, Vol. 18, No. 3, 08.2003, p. 473-485.

Research output: Contribution to journalArticle

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