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D. M. Inman, S. Baltan, D. J. Calkins, P. J. Horner; High IOP Decreases Compound Action Potential Amplitude and Leads to Preferential Loss of Physiologically Identified Small Caliber Axons in DBA/2 Optic Nerve. Invest. Ophthalmol. Vis. Sci. 2009;50(13):2769.
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The optic nerve degenerates in glaucoma. These studies were undertaken to gain insight into the timing and mechanism of glaucoma-induced optic neuropathy by contrasting electrophysiological observations with those of aging optic nerve before and after ischemic challenge.
Using the DBA/2J (D2) mouse model of glaucoma, we assessed optic nerve conduction in acutely isolated optic nerves from mice at 1, 6 and 10 months of age. C57Bl/6 mouse optic nerve (ON) served as control. Compound action potentials (CAP) were measured before and after nerve challenge with oxygen glucose deprivation (OGD) for 45 min or 1h. Immunohistochemical and Western blot analysis of optic nerve with antibodies against cytoskeletal proteins and membrane receptors was used to assess disease-related versus aging-related alterations in cellular or protein composition.
D2 optic nerves demonstrated IOP-dependent decreases in CAP amplitude at 6 months and radically diminished CAP amplitude by 10 months. The decreased CAP amplitude at 10 months in D2 included loss of the third, slow conducting axon CAP peak but not increased CAP latency, indicating loss of slow conducting axon populations as opposed to global dropout. Recovery of CAP amplitude after OGD was decreased in D2 ON at 6 and 10 months when compared to age-matched control optic nerve. CAP recovery after OGD was also correlated with IOP, but only at 6 months; lower IOP indicated greater CAP amplitude recovery after insult. The K+ channel blocker 4-aminopyrolidine had no effect on CAP amplitude in 6 month D2 optic nerve, suggesting that demyelination is not responsible for the declination in CAP amplitude. Protein and mRNA analysis of optic nerve indicated dramatic changes in the expression and distribution of neurofilament and internode proteins, including accumulation of protein at nodes of Ranvier. Increasing axon degeneration with age and raised IOP was concomitant with modest decreases in retinal ganglion cell (RGC) number.
Loss of slow conducting fibers in D2 optic nerve suggests greater impact of glaucomatous changes on smaller, lightly myelinated to unmyelinated retinal ganglion cell axons. The correlation of increased IOP with poorer outcome post-OGD only at 6 months may indicate a period of vulnerability where pressure negatively impacts axon resilience to metabolic challenge. ON physiological changes provide mechanistic insight for axon loss and occur upstream of significant RGC loss.
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