Synaptic Plasticity Restores Visual Responses and Protects from Degeneration-Induced Changes in the Zebrafish Retina

Humans are largely dependent upon cone-mediated vision. However, death or dysfunction of rods, the predominant photoreceptor subtype, results in secondary loss of cones, remodeling of retinal circuitry, and blindness. The changes in circuitry may contribute to the vision deficit and undermine attempts at restoring sight. I exploit zebrafish larvae as a genetic model to specifically characterize changes associated with photoreceptor degenerations in a cone-dominated retina. Photoreceptors form chemical synapses with two types of second-order neurons, bipolar cells, and horizontal cells. Using cell-specific reporter gene expression and immunolabeling for postsynaptic glutamate receptors, I demonstrate that significant remodeling is observed following cone degeneration in the pde6cw59 larval retina but not rod degeneration in the Xops:mCFPq13 line. In adults, rods and cones are present in approximately equal numbers. In Xops:mCFP q13 retinas, increased numbers of horizontal cell processes are observed increasing each cone pedicle. Surprisingly in pde6cw59 mutants, glutamate receptor expression and synaptic structures in the outer plexiform layer are also preserved, and visual responses are gained in these once-blind fish. I propose that the abundance of rods in the adult protects the retina from cone degeneration-induced remodeling. I test this hypothesis by genetically manipulating the number of rods in larvae. I show that an increased number and uniform distribution of rods in lor/tbx2bp25bbtl or six7 morpholino-injected larvae protect from pde6cw59-induced secondary changes. Ultrastructural evidence shows that the additional rods recruit postsynaptic processes and successfully form invaginating ribbon synapses in the outer plexiform layer. Combined, these results suggest that in photoreceptor degeneration, compensatory mechanisms lead to synapse formation between second order neurons and the available photoreceptors. Furthermore, the observation that in zebrafish a small number of surviving photoreceptors afford protection from degeneration-induced changes provides a model for systematic analysis of factors that slow or even prevent the secondary deteriorations associated with neural degenerative disease. This plasticity provides an avenue for maintaining proper retinal morphology and connectivity in the context of photoreceptor degenerations, which may be essential to facilitate attempts at restoring vision through retinal prostheses or stem cell therapies.