Selective loss of cone function in mice lacking the cyclic nucleotide-gated channel CNG3

Abstract

Two types of photoreceptors, rods and cones, coexist in the vertebrate retina. An in-depth analysis of the retinal circuitry that transmits rod and cone signals has been hampered by the presence of intimate physical and functional connections between rod and cone pathways. By deleting the cyclic nucleotide-gated channel CNG3 we have generated a mouse lacking any cone-mediated photoresponse. In contrast, the rod pathway is completely intact in CNG3-deficient mice. The functional loss of cone function correlates with a progressive degeneration of cone photoreceptors but not of other retinal cell types. CNG3-deficient mice provide an animal model to dissect unequivocally the contribution of rod and cone pathways for normal retinal function.

Modulation of rod photoreceptor output by HCN1 channels is essential for regular mesopic cone vision

“…In this assay, there was no sign of any cone system activity in HCN1 − / − mutants, either in the ON or the OFF pathway, despite the fact that cones were found to be functional in HCN1 − / − mutants in other paradigms 13 (confirmed by our findings below). In fact, the data closely resembled those of rod-only models like CNGA3 − / − lacking the cone cyclic nucleotide-gated channel subunit A3 and, therefore, having no functional cones 15,16 .…”

“…On the basis of a previous work 14 (and our unpublished data with this protocol in nob mice, N.T. and M.W.S), we knew that responses to low temporal frequency stimulation (0-3 Hz) are dominated by rod system activity, those to intermediate frequency stimulation (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15) by cone ON system activity, and those to high-frequency stimulation (≥15 Hz) by cone OFF system activity 15,16 . The ERG data in Figure 3a,b show that low frequency stimuli were well resolved in HCN1 − / − mice despite considerably prolonged responses, whereas, to our surprise, response amplitudes decreased dramatically with increasing frequency, and essentially no responses were observable above 5 Hz.…”

Hereditary Degenerative Retinopathies: Optimism for Somatic Gene Therapy

“…The resulting severe reduction in cation in ux and increase in production of oxygen radicals (because of the unloading of Na, K-ATPase pumps and reduction in oxygen consumption) may ultimately lead to apoptotic cell death. This supposition supported by the recent nding that mice lacking the cyclic nucleotide-gated channel showed selective loss of cone function (47 ). A similar mechanism can be proposed in the case of rhodopsin gene mutations (48)(49)(50).…”

Phototransduction in transgenic mice after targeted deletion of the rod transducin α-subunit

“…Deletion of Go␣ in the accessory olfactory bulb disrupts olfactory transduction and causes postnatal apoptosis of the primary sensory neurons (30). Null mutations in rhodopsin (31)(32)(33) or in the cyclicnucleotide-gated channel (34,35) cause the progressive loss of the photoreceptors. In contrast, knockout of Tr␣ precluded phototransduction, but few rods were lost.…”