Photoreceptor degeneration induces homeostatic rewiring of rod bipolar cells.

Retinitis pigmentosa (RP) is a constellation of genetically inherited diseases, most often caused initially by mutation of a rod photoreceptor gene and leading eventually to blindness.(1) Although the ultimate prognosis for RP is grim, many forms of the disease are slow to progress, with patients maintaining usable vision at least until middle age (for example, Berson et al.(2)(,)(3) and Hartong et al.(4)). Retinal circuits must therefore be able to adapt to photoreceptor loss,(5) though little is presently known about the cellular mechanisms mediating these alterations. Here, we show that in the rhodopsin knockout mouse (Rho(-/-)),(6) in which rods do not respond to light and degeneration proceeds slowly, rod bipolar cells (RBCs) in the absence of rod signaling reconnect to cones. RBCs in Rho(-/-) retinas have large-amplitude cone-driven responses, which are depolarizing and blocked by DL-AP4. Such responses were not observed in Gnat1(-/-) retinas also lacking rod light responses or in Elfn1(-/-) mice lacking functional synapses between rods and RBCs. Our single-cell recordings were supported by whole-retina electroretinograms, which indicated that most RBCs in Rho(-/-) retinas receive cone input but that little, if any, synaptic reorganization occurs in Gnat1(-/-) or Elfn1(-/-). Our observations suggest that the signal for RBC plasticity is neither the absence of a light response nor of a functional rod synapse but may be degeneration itself, perhaps through trophic effects caused by rod degeneration or some factor released by dying cells. VIDEO ABSTRACT.