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Michael L Risner, Silvia Pasini, David J Calkins; Retinal ganglion cell dendritic pruning in glaucoma is associated with early increased excitation. Invest. Ophthalmol. Vis. Sci. 2017;58(8):2541.
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© ARVO (1962-2015); The Authors (2016-present)
Glaucoma is linked to aging and sensitivity to intraocular pressure (IOP) that results in retinal ganglion cell (RGC) degeneration. A critical issue to resolve is the relationship between morphological and physiological events that occur early in progression, prior to outright degeneration of RGCs. Our goal in this study was to test how dendritic changes of distinct RGC types relate to physiological excitation, axonal transport to the brain, and correlative neurochemical changes in synaptic architecture.
In adult C57 mice IOP was increased by injecting microbeads into one eye and saline into the other eye. Following 2 or 4 weeks IOP elevation, brain and retinas were harvested. To assess RGC transport of cholera toxin subunit B coronal slices of the midbrain were made and sections of the superior colliculus were imaged. RGCs were filled with dye to recover morphology, whole-cell patch clamped while presenting flashes of light to measure RGC function, and immunolabeled for non-phosphorolated neurofilament H (NFH). RGCs were typified based on light response, dendritic stratification, and NFH labeling. Finally, retinal sections were labeled for the presynaptic ribbon synapse protein, RIBEYE, and postsynaptic protein PSD95.
Microbead occlusion increased IOP 30% above control (ctrl=39, 2,4wks=38, p<0.05). After 2 weeks of elevated IOP, transport to the SC decreased by 40% (ctrl=4, 2wk=7, p<0.05), indicating early axonopathy. Elevated IOP caused a decrease in dendritic field size and complexity in many RGC types (ON-OFF/ON (ctrl=24, 2wk=14, 4wk=17), ONS (ctrl=14, 2wk=9, 4wk=14), OFFT (ctrl=14, 2wk=4, 4 wk=8; p<0.05) at both time points. After 2 weeks elevated IOP RGCs showed no change in light-driven input current while light-evoked spike output increased for most RGC types (ON-OFF/OFF, ONS, OFFS (ctrl=9, 2wk=10, 4wk=6), OFFT, p<0.05). After 4 weeks of elevated IOP light-evoked input current decreased in OFFT and ON-OFF RGCs (p<0.05) and light-driven spike rate decreased for most RGCs (OFFT, ONS, ON-OFF/ON, p<0.05). Elevated IOP increased retinal RIBEYE at 2 weeks (ctrl=7, 2wks=7, p<0.05) with no change in PSD95 observed. After 4 weeks of elevated IOP we found no change in RIBEYE and a decrease in PSD95 (ctrl=6, 4wks=6, p<0.05).
RGC dendritic pruning due to increased IOP is associated with an early increase in excitation that is independent of ON vs OFF stratification.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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