ABSTRACT
The voltage-gated potassium channel responsible for controlling photoreceptor signaling is a heteromeric complex of Kv2.1 subunits with a regulatory Kv8.2 subunit. Kv2.1/Kv8.2 channels are localized to the photoreceptor inner segment and carry IKx, largely responsible for setting the photoreceptor resting membrane potential. Mutations in Kv8.2 result in childhood-onset Cone Dystrophy with Supernormal Rod Response (CDSRR). We generated a Kv8.2 knockout (KO) mouse and examined retinal signaling and photoreceptor degeneration to gain deeper insight into the complex phenotypes of this disease. Using electroretinograms we show that there is a tradeoff between delayed or reduced signaling from rods depending on the intensity of the light stimulus, consistent with reduced capacity for light-evoked changes in membrane potential. The delayed response was not seen ex vivo where extracellular potassium levels are the same, so we conclude the in vivo alteration is influenced by ionic imbalance. We observed mild retinal degeneration. Signaling from cones was reduced but there was no loss of cone density. Loss of Kv8.2 altered responses to flickering light with responses attenuated at high frequencies and altered in shape at low frequencies. The Kv8.2 KO line on an all-cone retina background had reduced cone signaling associated with degeneration. We conclude that Kv8.2 is required by rods and cones for responding to dynamic changes in lighting. The timing and cell type affected by degeneration is different in the mouse and human but there is a window of time in both for therapeutic intervention.
SIGNIFICANCE STATEMENT Cone Dystrophy with Supernormal Rod Responses is a poorly understood form of blindness caused by mutations in Kv8.2, a regulatory potassium channel subunit that participates in setting the resting membrane potential of photoreceptors. We provide an in-depth analysis of retinal signaling and photoreceptor health when Kv8.2 is absent from the normal mouse retina or from an all-cone mouse retina. Rods maintain signaling by making trade-offs in response amplitude or timing. Diminished signaling from cones is independent of the supernormal responses from rods. There is a mild degeneration of rods, but cones are preserved so long as rods are present. Our observations provide insight into how a deficit in the dark current of photoreceptors prevents normal photoresponses.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
CONFLICT OF INTEREST STATEMENT: The authors declare no competing financial interests.
ABBREVIATIONS
- CDSRR
- Cone Dystrophy with Supernormal Rod Responses
- KCNV2
- Potassium voltage-gated channel modifier subfamily V member 2
- KCNB1
- Potassium voltage-gated channel subfamily B member 1
- Kv8.2
- Voltage-gated potassium channel subunit 8.2
- Kv2.1
- Voltage-gated potassium channel subunit 2.1
- ISEV
- International Society for Clinical Electrophysiology of Vision
- ERG
- electroretinography
- OCT
- optical coherence tomography
- HCN1
- Hyperpolarization and cyclic nucleotide-gated channel, family member 1
- NKA
- Sodium-potassium ATPase
- RPE
- Retinal pigment epithelium
- OS
- Outer segment
- IS
- Inner segment
- OLM
- Outer limiting membrane
- ONL
- Outer nuclear layer
- OPL
- Outer plexiform layer
- INL
- Inner nuclear layer
- IPL
- Inner plexiform layer
- GC
- Ganglion cell layer
- CC
- Connecting Cilium
- BB
- Basal body
- N
- Nucleus