Connexin 36-dependent retinal function in mice with specific rod or cone photoreceptor input

Purpose: To analyze the impact of the lack of connexin36 (Cx36) on retinal function. For this purpose, rod and cone photoreceptor input was separated by means of double mutant mice deficient of Cx36 plus either Rho (rod opsin knockout, cone function only) or Cnga3 (cone cyclic nucleotide-gated channel knockout, rod function only). Methods: Double mutant mice were generated by cross-breeding Cx36-/- mice with either Rho-/- or Cnga3-/- animals. The resulting double knockouts in the F2 were identified by RT-PCR. Mice were studied by scotopic and photopic electroretinography (ERG) using previously reported protocols (Saszik et al., J Physiol 2002; 543.3: 899-916, and Seeliger et al., Nat Genet 2001; 29: 70-74). Results: In comparison to wild type animals, Cx36-deficient mice show clear abnormalities in the ERG. For very low stimulus strengths, the negative scotopic threshold response was absent. The most dramatic change in the scotopic recordings was observed in the oscillatory potentials (OPs) riding on the b-wave, which were reduced at low stimulus strengths up to 10-2 cds/m², about normal in an intermediate range, and completely absent at the highest stimulus strengths above 3-10 cds/m². OPs were also strongly reduced in photopic ERG. If the input to the retina was limited to rods (i.e. in the double knockouts with the Cnga3 model), the scotopic results were largely comparable to those in a single Cx36-/- mouse, indicating that the loss of the OPs observed is cone-independent. In both rod and cone-specific recordings, the basal amplitudes of the b-wave not including the OPs were within normal limits. Conclusions: The connexin36 knockout model was found to have at least two functional phenotypes. At very low stimulus intensities, the missing coupling of the AII amacrine cells in the inner retina may lead to reduced OPs and a loss of the scotopic threshold response. At high intensities, the missing coupling, perhaps in outer retina, causes a dramatic change to the rod-driven OPs that occur in response to very strong stimuli