Abstract
Purpose :
Cone Dystrophy with Supernormal Rod Response (CDSRR) is a rare autosomal recessive disease, leading to severe visual impairment in humans, but little is known about the pathophysiology of this disorder. It is known to be caused by mutations in the KCNV2 gene which encodes the Kv8.2 subunit, a modulatory subunit of a voltage-gated potassium (Kv) channel. A hallmark of CDSRR is the depressed a-wave and supernormal b-wave electroretinogram (ERG) response. This study used Kv subunits knockout mice to further study the disease mechanism.
Methods :
To determine the role of Kv channels in the regulation of electrophysiological response of the retina to light as well as molecular and physiological changes arising from the loss of channels, we first examined the cellular localization, gene expression and functional properties of Kv8.2 and its channel co-partner subunit, Kv2.1, in knockout (KO) and wild-type (WT) mouse models. Ex vivo retinal ERG recordings were used to evaluate the scotopic physiological response to light intensities in Kv8.2 and WT mouse retinas under normal conditions and after delivery of a potassium channel blocker.
Results :
The Kv8.2 subunit is exclusively expressed in outer/inner segment of mouse photoreceptors and co-localizes with both cone and rod photoreceptors. We show that Kv8.2 KO retinas have significantly higher apoptotic cells (p=0.006), thinner outer nuclear cell layer (p=0.04) and increased activated microglia cells (p=0.0074) when compared to WT retinas. Our data indicates that the loss of Kv8.2 subunits induces photoreceptors death, thinning of the outer nuclear layer and activation of retinal microglia response. Using ex vivo ERG recordings and pharmacology, we show that the Kv8.2 mouse model has a similar electrophysiological phenotype as seen in CDSRR patients. Interestingly, our results show that only WT retinas are affected by applying a Kv channel blocker, which suppresses the generation of the b-wave. However, there is not a significant difference in the ERG response of Kv8.2 KO retinas between drug and non-drug application (p=0.54).
Conclusions :
All these characteristics indicate that the Kv8.2 KO mouse model mimics the clinical features seen in CDSRR patients and would provide a useful model for elucidating the disease mechanisms, the role of Kv channels in the visual cascade and for validating treatment approaches for CDSRR.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.