Oligodendrocyte dysfunction after induction of experimental anterior optic nerve ischemia.
OBJECTIVE
The early response and survival of oligodendrocytes after axonal stroke and their potential contribution to neuronal survival in vivo have not been adequately addressed. The purpose of this study was to investigate the changes occurring in the retina and optic nerve (ON) in anterior ischemic optic neuropathy (AION), using a c-fos transgenic mouse model.


METHODS
A new mouse model of AION (rodent AION) was developed to evaluate the in vivo stress response of oligodendrocytes and retinal ganglion cells (RGCs) in a transgenic mouse strain, using the immediate early stress-response gene c-fos, RT-QPCR technology, immunohistochemistry, and electron microscopy. Confocal microscopy was used with cell-specific antibodies to characterize the timing of cells responding to rAION. The TUNEL assay detected cells undergoing apoptosis. Ultrastructural changes were analyzed by electron microscopy.


RESULTS
In rAION, oligodendrocytes rapidly respond in vivo to ischemic ON damage, with c-fos activation as an early detectable event. Early evidence of progressive oligodendrocyte stress, is followed by demyelination, wallerian degeneration of the ON, and oligodendrocyte and RGC death far from the primary lesion.


CONCLUSIONS
After rAION induction oligodendrocytes, as well as RGCs, undergo progressive stress, with dysfunction and apoptosis. The findings lead to a proposal that progressive retrograde oligodendrocyte stress, away from the primary lesion, is an important factor after ischemic optic neuropathy. Postinduction demyelination must be addressed for effective neuroprotection of ischemic and hypoxic white matter.
Goldenberg-Cohen
Nitza
N
Wilmer Ophthalmological Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21201, USA.
Guo
Yan
Y
Margolis
Frank
F
Cohen
Yoram
Y
Miller
Neil R
NR
Bernstein
Steven L
SL
D000818:Animals; D017209:Apoptosis; D004195:Disease Models, Animal; D005451:Fluorescein Angiography; D016762:Genes, fos / Q000235:genetics; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D004676:Myelin Basic Protein / Q000378:metabolism; D009836:Oligodendroglia / Q000378:metabolism / Q000473:pathology*; D009900:Optic Nerve / Q000378:metabolism / Q000473:pathology*; D018917:Optic Neuropathy, Ischemic / Q000378:metabolism / Q000473:pathology*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D012160:Retina / Q000473:pathology; D012165:Retinal Ganglion Cells / Q000378:metabolism / Q000473:pathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D004676:Myelin Basic Protein; D016760:Proto-Oncogene Proteins c-fos