Using gene therapy to probe the circuit for color vision

Abstract

We have successfully treated color blindness in an adult primate using gene therapy. This raises the major question of what are the properties of the neural circuit that make the addition of a new dimension of color vision possible. Toward answering this, we probed the circuit for color vision in the rodent using a gene therapy approach in which new long-wavelength sensitivity was targeted to either S-cone or M-cone pathways. Gene therapy using cone-class specific transcriptional regulatory elements enabled us to express human L-opsin in a mosaic of either M- or S-cones. Functional consequences of the expanded spectral sensitivity were explored after therapy by measuring the neuronal response throughout the visual system with fMRI and behavioral tests of color vision. Dramatic expansion of color vision to include a red-green dimension of color vision in these rodents was observed when L-opsin was targeted to S-cones but not when targeted to M-cones. This result indicates that the novel red-green color vision observed in animals treated with gene therapy is served by a portion of the preexisting circuit for blue-yellow color vision involving the S-cone pathway. This implies that the expanded color vision was generated with a change only at the receptor level with gene therapy, without plastic neural changes in high-order cortical or subcortical circuitry. This presumably parallels the origins of the circuit for red-green color vision in primates which must have arisen from a preexisting circuit serving blue-yellow color vision rather than from evolution of a new circuit de novo.