July 2019
Volume 60, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2019
Coupling architecture of the Aii/ON cone bipolar cell network in degenerate retina
Author Affiliations & Notes
  • Crystal Sigulinsky
    Ophthalmology & Visual Sciences, University of Utah, Salt Lake City, Utah, United States
  • Rebecca L Pfeiffer
    Ophthalmology & Visual Sciences, University of Utah, Salt Lake City, Utah, United States
  • James Anderson
    Ophthalmology & Visual Sciences, University of Utah, Salt Lake City, Utah, United States
  • Daniel Emrich
    Ophthalmology & Visual Sciences, University of Utah, Salt Lake City, Utah, United States
  • Christopher Rapp
    Ophthalmology & Visual Sciences, University of Utah, Salt Lake City, Utah, United States
  • Jeebika Dahal
    Ophthalmology & Visual Sciences, University of Utah, Salt Lake City, Utah, United States
  • Jessica Garcia
    Ophthalmology & Visual Sciences, University of Utah, Salt Lake City, Utah, United States
  • Hope Morrison
    Ophthalmology & Visual Sciences, University of Utah, Salt Lake City, Utah, United States
  • Kevin Rapp
    Ophthalmology & Visual Sciences, University of Utah, Salt Lake City, Utah, United States
  • Jia-Hui Yang
    Ophthalmology & Visual Sciences, University of Utah, Salt Lake City, Utah, United States
  • Carl Watt
    Ophthalmology & Visual Sciences, University of Utah, Salt Lake City, Utah, United States
  • Mineo Kondo
    Ophthalmology, Mie University Graduate School of Med, Japan
  • Hiroko Terasaki
    Ophthalmology, Nagoya Univ School of Medicine, Japan
  • Robert Marc
    Ophthalmology & Visual Sciences, University of Utah, Salt Lake City, Utah, United States
  • Bryan W Jones
    Ophthalmology & Visual Sciences, University of Utah, Salt Lake City, Utah, United States
  • Footnotes
    Commercial Relationships   Crystal Sigulinsky, None; Rebecca Pfeiffer, None; James Anderson, None; Daniel Emrich, None; Christopher Rapp, None; Jeebika Dahal, None; Jessica Garcia, None; Hope Morrison, None; Kevin Rapp, None; Jia-Hui Yang, None; Carl Watt, None; Mineo Kondo, None; Hiroko Terasaki, None; Robert Marc, Signature Immunologics Inc. (I); Bryan Jones, None
  • Footnotes
    Support  R01 Grant EY015128, R01 Grant EY02576, T32 Grant EY024234, P30 Grant EY014800, Undergraduate research awards from the Undergraduate Research Opportunities Program at the University of Utah, Unrestricted Grant from Research to Prevent Blindness to the Department of Ophthalmology & Visual Sciences
Investigative Ophthalmology & Visual Science July 2019, Vol.60, 6441. doi:https://doi.org/
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      Crystal Sigulinsky, Rebecca L Pfeiffer, James Anderson, Daniel Emrich, Christopher Rapp, Jeebika Dahal, Jessica Garcia, Hope Morrison, Kevin Rapp, Jia-Hui Yang, Carl Watt, Mineo Kondo, Hiroko Terasaki, Robert Marc, Bryan W Jones; Coupling architecture of the Aii/ON cone bipolar cell network in degenerate retina. Invest. Ophthalmol. Vis. Sci. 2019;60(9):6441. doi: https://doi.org/.

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

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Abstract

Purpose : In mouse models of retinal degeneration, connexin36-containing gap junctions in the Aii amacrine cell network appear to mediate aberrant hyperactivity within the retina. However, it remains unclear whether this hyperactivity reflects changes in the underlying circuitry or dysfunction of the normative circuitry. Our connectomics-based mapping of retinal circuitry in rabbit Retinal Connectome 1 (RC1) has dramatically expanded the coupled Aii network. In addition to canonical Aii-to-Aii and Aii-to-ON cone bipolar cell (CBC) coupling, we describe pervasive in- and cross-class coupling motifs among ON CBCs. This study examines the changes in these coupling motifs in RPC1, an ultrastructural retinal pathoconnectome from a rabbit model of retinitis pigmentosa.

Methods : RC1 and RPC1 are connectomes built by automated transmission electron microscopy at ultrastructural (2 nm/pixel) resolution. RC1 is a 0.25 mm diameter volume of retina from a 13 month old, light-adapted female Dutch Belted rabbit and serves as the healthy reference connectome. RPC1 is a 0.09 mm diameter volume of pathological retina from a 10 month old, male transgenic P347L model of autosomal dominant retinitis pigmentosa showing early phase 1 retinal remodeling, when rod photoreceptors are still present, but stressed. ON CBCs, Aii amacrine cells, and their coupling partners were annotated using the Viking application. Coupling motifs and features were explored with 3D rendering and graph visualization of connectivity. Gap junctions were validated by 0.25 nm resolution recapture with goniometric tilt when necessary.

Results : All major coupling motifs were observed. Several ON CBC classes retained their class-specific coupling profiles, accepting and rejecting specific combinations of Aii and ON CBC class partnerships. However, aberrant partnerships exist in the coupled network, including both loss of prominent motifs and acquisition of novel ones.

Conclusions : Clearly aberrant morphological and synaptic changes exist in RPC1, including changes in the coupling specificity and gap junction distributions of both Aii amacrine cells and ON CBCs. This indicates that the Aii/ON CBC circuit topology is already altered during early phase 1 remodeling, with substantial implications for therapeutic interventions for blinding diseases that depend upon the surviving retinal network in human patients.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.

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