Rewiring of photoreceptor cell synapses following rod or cone degeneration in zebrafish

Abstract

Purpose: We have previously shown in the cone-dominated larval zebrafish retina that significant alterations of bipolar cell processes are observed following cone but not rod degeneration. Conditions that increase the number of surviving photoreceptors provide protection from degeneration-induced histological changes and can restore vision. The goal of this study is to determine what specific remodeling in photoreceptor synaptic organization and horizontal cell structure occurs following selective loss of rod or cone photoreceptors.

Methods: Two zebrafish genetic models of photoreceptor degeneration were used: the Xops:mCFP^q13 transgenic line results in the exclusive death of rods, and the pde6c^w59 line exhibits cone degeneration. The number of rods in pde6c^w59 animals was increased using a six7 antisense morpholino. Electron microscopy was used for ultrastructural analyses of photoreceptor synapses. Horizontal cells were visualized by DiI labeling or by immunolabeling for dendritic glutamate receptors. Confocal microscopy was utilized to examine changes in horizontal cell morphology and photoreceptor synaptic structure.

Results: Immunolabeling revealed that cone terminals in the rodless Xops:mCFP^q13 retinas have an increased diameter and contact a greater number of GluR2-positive dendrites than wildtype retinas. These data suggest that in the absence of rods, rod horizontal cells make new contacts with the available cone terminals. Similarly, the greater number and regular distribution of rods in the pde6c^w59/six7 morphant retinas were associated with increased labeling for postsynaptic structures compared to pde6c^w59 alone. Ultrastructural analysis revealed that in the absence of cones, second order neurons make contacts with the available rods. Synaptic triads consisting of a presynaptic ribbon in the rod terminals and lateral and central postsynaptic processes were observed.

Conclusions: These data show that in response to rod or cone degeneration, horizontal cell dendrites are recruited by the remaining photoreceptor cell type. This suggests that in the zebrafish outer retina, synapses rewire to accommodate changes in afferent cell type, their number and distribution. This plasticity provides an avenue for maintaining proper morphology and connectivity in the context of photoreceptor degenerations, which may be essential to facilitate attempts at restoring vision through retinal prostheses.

Keywords: 689 retina: distal (photoreceptors, horizontal cells, bipolar cells) • 728 synapse • 615 neuroprotection