Abstract
Purpose :
The objective of this study was to assess the role of voltage-gated potassium channels in phototransduction. A unique form of cone-rod dysfunction arises from mutations in the KCNV2 gene which encodes the voltage-gated potassium channel subunit Kv8.2. The ERG shows a severe reduction in a- and b-wave amplitudes at lower light intensities which changes to an enhanced b-wave at higher intensities. Kv8.2 only forms functional channels with another channel protein, Kv2.1, encoded by KCNB1. We now have characterised the retinal phenotype of knock-out (KO) mouse models for both genes and the double KO.
Methods :
Mouse KOs for kcnv2 (Kv8.2) and kcnb1 (Kv2.1) were assessed for scotopic and photopic ERG responses. Retinal histology was examined by OCT, cone loss by immunohistochemistry with cone arrestin antibody, cell death by TUNEL, and expression of kcnv2 and kcnb1 by qPCR.
Results :
A mild reduction in the overall thickness of retinae of KO mice is due largely to reductions in the outer nuclear and photoreceptor layers. Cell death is also moderately increased in KO mice, with only a 20% loss of cones. The ERG in Kv8.2 KO mice is severely depressed at low flash intensities but flips to an enhanced response at higher intensities. At all intensities, the implicit time for the b-wave is prolonged. The Kv2.1 and double KO mice show similar patterns, although in neither case is there an enhanced response. The a-wave in all three KO lines remains severely depressed, and the c-wave is totally absent. Photopic flicker is also reduced but only marginally delayed.
Conclusions :
These results validate the Kv8.2 KO as a good model of the human disorder. Loss of functional Kv2.1 subunits results in a similar phenotype to the Kv8.2 KO, although responses to light flashes remain depressed at all intensities. In both mouse models, the a-wave is severely reduced, and this contributes substantially to the reduced scotopic response. The loss of photoreceptors is mild; this disorder may be a good candidate therefore for gene therapy.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.