Coupling Architecture Of The AII/ON Cone Bipolar Cell Network In Degenerate Retina

This abstract was presented today, April 8th at the 2019 Association for Research in Vision and Opthalmology (ARVO) meetings in Vancouver, Canada as a platform presentation by Crystal L. Sigulinsky, Rebecca L. PfeifferJames R. Anderson, Daniel P. Emrich, Christopher Rapp, Jeebika Dahal, Jessica Garcia, Hope Morrison, Kevin D. Rapp, Jia-Hui Yang, Carl B. Watt, Robert E. Marc and Bryan W. Jones.

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.

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