Abstract
Abstract: :
Purpose: Our goal was to explore the nature and scope of anomalous rewiring in microneuromas formed during retinal remodeling in late–stage retinal degenerations. Methods: Serial section ultrastructural computational molecular phenotyping (Jones et al. 2003 J Comp Neurol 464: 116) in the RCS (mertk) rat model of inherited retinal degeneration was performed on retinal microneuromas in PND 200–900 animals. Ultrastructural data were acquired from high resolution film–imaging of 90 nm sections and GABA, glycine, taurine and glutamate signals acquired from flanking 40 nm optical sections. Datasets were visualized as rgb and theme maps of classified cell types, and the emergent circuits modeled. Results: Thousands of small synaptic aggregates (microneuromas) are formed de novo in the remnant inner nuclear layer of the remodeling rodent retina. Serially reconstructed microneuromas reveal important key features. (1) All types of neurons can contribute terminal processes to a microneuroma. One microneuroma contained 36 separate processes, including BCs, GCs, glycinergic ACs and GABAergic ACs, most of which made synapses and terminated in the microneuroma. (2) A new process can be both pre– and post–synaptic. The figure shows partial circuitry of a reconstructed microneuroma. BC1 sends processes into both the microneuroma and the IPL, engaging in numerous presynaptic and postsynaptic assemblies. Included in this array is the anomalous chain of BC0 → BC1 → BC15 → γAC6 → BC1. Modeling of such circuits shows high instability and resonant activity. (3) Microneuromas are also connected to the inner plexiform layer (IPL). BCs with extensive IPL connections also send single processes into microneuromas where they form and receive synapses. Conclusions: Rewiring in retinal degenerations includes novel microneuromas wherein extensive new synaptic forms emerge. There is little evidence that microneuromas recapitulate normal wiring, and much evidence of anomalous corruptive wiring. These data are consistent with the hypothesis that recovery of excitatory inputs is key to neuronal survival in retinal degenerations.
Keywords: retinal degenerations: cell biology • retinal connections, networks, circuitry • plasticity