Entorhinal Cortex Lesion in the Mouse Induces Transsynaptic Death of Perforant Path Target Neurons

Entorhinal cortex lesion (ECL) is a well described model of anterograde axonal degeneration, subsequent sprouting and reactive synaptogenesis in the hippocampus. Here, we show that such lesions induce transsynaptic degeneration of the target cells of the lesions pathway in the dentate gyrus. Peaking...

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Published in:Brain pathology (Zurich, Switzerland) Switzerland), 2004-07, Vol.14 (3), p.249-257
Main Authors: Kovac, Adam D., Kwidzinski, Erik, Heimrich, Bernd, Bittigau, Petra, Deller, Thomas, Nitsch, Robert, Bechmann, Ingo
Format: Article
Language:English
Subjects:
Animals
Apoptosis - physiology
Axotomy
Caspase 3
Caspases - drug effects
Caspases - metabolism
Dizocilpine Maleate - pharmacology
Entorhinal Cortex - pathology
Enzyme Activation - drug effects
Excitatory Amino Acid Antagonists - pharmacology
Fas Ligand Protein
fas Receptor - metabolism
Glutamic Acid - metabolism
Immunohistochemistry
Male
Membrane Glycoproteins - metabolism
Mice
Microscopy, Electron
Neurons - pathology
Perforant Pathway - pathology
Synapses - physiology
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Summary:Entorhinal cortex lesion (ECL) is a well described model of anterograde axonal degeneration, subsequent sprouting and reactive synaptogenesis in the hippocampus. Here, we show that such lesions induce transsynaptic degeneration of the target cells of the lesions pathway in the dentate gyrus. Peaking between 24 and 36 hours postlesion, dying neurons were labeled with DeOlmos silver‐staining and antisera against activated caspase 3 (CCP32), a downstream inductor of programmed cell death. Within caspase 3‐positive neurons, fragmented nuclei were co‐localized using Hoechst 33342 staining. Chromatin condensation and nuclear fragmentation were also evident in semithin sections and at the ultrastructural level, where virtually all caspase 3‐positive neurons showed these hallmarks of apoptosis. There is a well‐described upregulation of the apoptosis‐inducing CD95/L system within the CNS after trauma, yet a comparison of caspase 3‐staining patterns between CD95 (lpr)‐ and CD95L (gld)‐deficient with non‐deficient mice (C57/bl6) provided no evidence for CD95L‐mediated neuronal cell death in this setting. However, inhibition of NMD A receptors with MK‐801 completely suppressed caspase 3 activation, pointing to glutamate neurotoxicity as the upstream inducer of the observed cell death. Thus, these data show that axonal injury in the CNS does not only damage the axotomized neurons themselves, but can also lethally affect their target cells, apparently by activating glutamate‐mediated intracellular pathways of programmed cell death.
ISSN:1015-6305
1750-3639
DOI:10.1111/j.1750-3639.2004.tb00061.x