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Axogenic mechanism enhances retinal ganglion cell excitability during early progression in glaucoma.
Proc Natl Acad Sci U S A. 2018 03 06; 115(10):E2393-E2402.PN

Abstract

Diseases of the brain involve early axon dysfunction that often precedes outright degeneration. Pruning of dendrites and their synapses represents a potential driver of axonopathy by reducing activity. Optic nerve degeneration in glaucoma, the world's leading cause of irreversible blindness, involves early stress to retinal ganglion cell (RGC) axons from sensitivity to intraocular pressure (IOP). This sensitivity also influences survival of RGC dendrites and excitatory synapses in the retina. Here we tested in individual RGCs identified by type the relationship between dendritic organization and axon signaling to light following modest, short-term elevations in pressure. We found dendritic pruning occurred early, by 2 wk of elevation, and independent of whether the RGC responded to light onset (ON cells) or offset (OFF cells). Pruning was similarly independent of ON and OFF in the DBA/2J mouse, a chronic glaucoma model. Paradoxically, all RGCs, even those with significant pruning, demonstrated a transient increase in axon firing in response to the preferred light stimulus that occurred on a backdrop of generally enhanced excitability. The increased response was not through conventional presynaptic signaling, but rather depended on voltage-sensitive sodium channels that increased transiently in the axon. Pruning, axon dysfunction, and deficits in visual acuity did not progress between 2 and 4 wk of elevation. These results suggest neurodegeneration in glaucoma involves an early axogenic response that counters IOP-related stress to excitatory dendritic architecture to slow progression and maintain signaling to the brain. Thus, short-term exposure to elevated IOP may precondition the neural system to further insult.

Authors+Show Affiliations

Department of Ophthalmology and Visual Sciences, Vanderbilt University Medical Center, Nashville, TN 37232-0654.Department of Ophthalmology and Visual Sciences, Vanderbilt University Medical Center, Nashville, TN 37232-0654.Department of Ophthalmology and Visual Sciences, Vanderbilt University Medical Center, Nashville, TN 37232-0654.Department of Ophthalmology and Visual Sciences, Vanderbilt University Medical Center, Nashville, TN 37232-0654.Department of Ophthalmology and Visual Sciences, Vanderbilt University Medical Center, Nashville, TN 37232-0654 david.j.calkins@vanderbilt.edu.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29463759

Citation

Risner, Michael L., et al. "Axogenic Mechanism Enhances Retinal Ganglion Cell Excitability During Early Progression in Glaucoma." Proceedings of the National Academy of Sciences of the United States of America, vol. 115, no. 10, 2018, pp. E2393-E2402.
Risner ML, Pasini S, Cooper ML, et al. Axogenic mechanism enhances retinal ganglion cell excitability during early progression in glaucoma. Proc Natl Acad Sci U S A. 2018;115(10):E2393-E2402.
Risner, M. L., Pasini, S., Cooper, M. L., Lambert, W. S., & Calkins, D. J. (2018). Axogenic mechanism enhances retinal ganglion cell excitability during early progression in glaucoma. Proceedings of the National Academy of Sciences of the United States of America, 115(10), E2393-E2402. https://doi.org/10.1073/pnas.1714888115
Risner ML, et al. Axogenic Mechanism Enhances Retinal Ganglion Cell Excitability During Early Progression in Glaucoma. Proc Natl Acad Sci U S A. 2018 03 6;115(10):E2393-E2402. PubMed PMID: 29463759.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Axogenic mechanism enhances retinal ganglion cell excitability during early progression in glaucoma. AU - Risner,Michael L, AU - Pasini,Silvia, AU - Cooper,Melissa L, AU - Lambert,Wendi S, AU - Calkins,David J, Y1 - 2018/02/20/ PY - 2018/2/22/pubmed PY - 2018/10/31/medline PY - 2018/2/22/entrez KW - axonopathy KW - dendritic pruning KW - glaucoma KW - neurodegeneration KW - retinal ganglion cells SP - E2393 EP - E2402 JF - Proceedings of the National Academy of Sciences of the United States of America JO - Proc Natl Acad Sci U S A VL - 115 IS - 10 N2 - Diseases of the brain involve early axon dysfunction that often precedes outright degeneration. Pruning of dendrites and their synapses represents a potential driver of axonopathy by reducing activity. Optic nerve degeneration in glaucoma, the world's leading cause of irreversible blindness, involves early stress to retinal ganglion cell (RGC) axons from sensitivity to intraocular pressure (IOP). This sensitivity also influences survival of RGC dendrites and excitatory synapses in the retina. Here we tested in individual RGCs identified by type the relationship between dendritic organization and axon signaling to light following modest, short-term elevations in pressure. We found dendritic pruning occurred early, by 2 wk of elevation, and independent of whether the RGC responded to light onset (ON cells) or offset (OFF cells). Pruning was similarly independent of ON and OFF in the DBA/2J mouse, a chronic glaucoma model. Paradoxically, all RGCs, even those with significant pruning, demonstrated a transient increase in axon firing in response to the preferred light stimulus that occurred on a backdrop of generally enhanced excitability. The increased response was not through conventional presynaptic signaling, but rather depended on voltage-sensitive sodium channels that increased transiently in the axon. Pruning, axon dysfunction, and deficits in visual acuity did not progress between 2 and 4 wk of elevation. These results suggest neurodegeneration in glaucoma involves an early axogenic response that counters IOP-related stress to excitatory dendritic architecture to slow progression and maintain signaling to the brain. Thus, short-term exposure to elevated IOP may precondition the neural system to further insult. SN - 1091-6490 UR - https://www.unboundmedicine.com/medline/citation/29463759/Axogenic_mechanism_enhances_retinal_ganglion_cell_excitability_during_early_progression_in_glaucoma_ L2 - http://www.pnas.org/cgi/pmidlookup?view=long&pmid=29463759 DB - PRIME DP - Unbound Medicine ER -