June 2021
Volume 62, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2021
Expanding the view: large-scale assessment of synaptic disassembly in experimental glaucoma
Author Affiliations & Notes
  • Manuel Soliño
    Ophthalmology, University of California San Francisco, San Francisco, California, United States
  • Alfred K Yu
    Ophthalmology, University of California San Francisco, San Francisco, California, United States
  • Luca Della Santina
    Ophthalmology, University of California San Francisco, San Francisco, California, United States
  • Yvonne Ou
    Ophthalmology, University of California San Francisco, San Francisco, California, United States
  • Footnotes
    Commercial Relationships   Manuel Soliño, None; Alfred Yu, None; Luca Della Santina, None; Yvonne Ou, None
  • Footnotes
    Support  NIH-NEI EY028148 / That Man May See Foundation / NIH-NEI P30 EY002162 / Research to Prevent Blindness
Investigative Ophthalmology & Visual Science June 2021, Vol.62, 3137. doi:
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    • Get Citation

      Manuel Soliño, Alfred K Yu, Luca Della Santina, Yvonne Ou; Expanding the view: large-scale assessment of synaptic disassembly in experimental glaucoma. Invest. Ophthalmol. Vis. Sci. 2021;62(8):3137.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose :
As synapse loss is an early biomarker in experimental glaucoma, we studied the temporal dynamics of synapse disassembly in the entire inner plexiform layer (IPL) at varying time points after transient ocular hypertension.

Methods : Unilateral intraocular pressure elevation was induced in adult CD-1 mice by laser photocoagulation of the limbal and episcleral vessels, and then sacrificed at 7d, 14d, and 30d. Retinas were processed as wholemounts and stained by immunohistochemistry against Brn3a (ganglion cell marker), CtBP2 (ribbon marker), PSD95 (postsynaptic marker), and TO-PRO-3 (nuclear marker). Four confocal image stacks of the entire IPL depth of each retina were obtained. We quantified pre and postsynaptic puncta and their spatial relationships. Statistical analysis was performed using mixed effects analysis.

Results :
We found that ribbon density drops at 30d (Mixed-effects analysis, p=0.001). PSD95 density also drops, significantly at 14d and 30d (Mixed-effects analysis, p=0.024 and p=0.018, respectively). When assessing synaptic puncta density as a function of IPL depth, we found that ribbon density progressively drops at 14d and 30d at most IPL depths but density is preserved or recovers in the ON sublamina (Mixed-effects analysis, p<0.0001 for IPL depth and time as fixed effects). Conversely, when assessed as a function of IPL depth, postsynaptic proteins appear more resilient to transient ocular hypertension. The maximum decrease of PSD95 density occurs at 14d and partially recovers by 30d (Mixed-effects analysis, p<0.0001). Again, the ON sublamina shows less damage than the OFF sublamina (Mixed-effects analysis, p<0.0001).

Conclusions :
Although the initial site of injury in glaucomatous neurodegeneration is thought to be axonal compression at the optic nerve head, we show that bipolar cell ribbons are lost earlier and to a greater degree than their postsynaptic counterpart PSD95. This raises the possibility that bipolar cells are an active participant in the degeneration process. We also show that this process of synapse disassembly is non-uniform across IPL sublaminae, potentially resulting in differential impairment of distinct functional sub-circuits.

This is a 2021 ARVO Annual Meeting abstract.

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