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Purpose The R345W mutation in EFEMP1 causes malattia leventinese, an autosomal dominant eye disease with pathogenesis similar to an early-onset age-related macular degeneration. In mice, Efemp1R345W does not cause detectable degeneration but small subretinal deposits do accumulate. The purpose of this study was to determine whether there were abnormal responses to light at this presymptomatic stage in Efemp1R345W mice. Methods Responses to light were assessed by visual water task, circadian phase shifting, and negative masking behavior. The mechanism of abnormal responses was investigated by anterior eye exam, electroretinogram, melanopsin cell quantification, and multielectrode recording of retinal ganglion cell activity. Results Visual acuity was not different in Efemp1R345W mice. However, amplitudes of circadian phase shifting (P = 0.016) and negative masking (P < 0.0001) were increased in Efemp1R345W mice. This phenotype was not explained by anterior eye defects or amplified outer retina responses. Instead, we identified increased melanopsin-generated responses to light in the ganglion cell layer of the retina (P < 0.01). Conclusions Efemp1R345W increases the sensitivity to light of behavioral responses driven by detection of irradiance. An amplified response to light in melanopsin-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs) is consistent with this phenotype. The major concern with this effect of the malattia leventinese mutation is the potential for abnormal regulation of physiology by light to negatively affect health.

PURPOSE In animal models of degenerative photoreceptor disease, there has been some success in restoring photoreception by transplanting stem cell-derived photoreceptor cells into the subretinal space. However, only a small proportion of transplanted cells develop extended outer segments, considered critical for photoreceptor cell function. The purpose of this study was to determine whether photoreceptor cells that lack a fully formed outer segment could usefully contribute to vision. METHODS Retinal and visual function was tested in wild-type and Rds mice at 90 days of age (Rds(P90)). Photoreceptor cells of mice homozygous for the Rds mutation in peripherin 2 never develop a fully formed outer segment. The electroretinogram and multielectrode recording of retinal ganglion cells were used to test retinal responses to light. Three distinct visual behaviors were used to assess visual capabilities: the optokinetic tracking response, the discrimination-based visual water task, and a measure of the effect of vision on wheel running. RESULTS Rds(P90) mice had reduced but measurable electroretinogram responses to light, and exhibited light-evoked responses in multiple types of retinal ganglion cells, the output neurons of the retina. In optokinetic and discrimination-based tests, acuity was measurable but reduced, most notably when contrast was decreased. The wheel running test showed that Rds(P90) mice needed 3 log units brighter luminance than wild type to support useful vision (10 cd/m(2)). CONCLUSIONS Photoreceptors that lack fully formed outer segments can support useful vision. This challenges the idea that normal cellular structure needs to be completely reproduced for transplanted cells to contribute to useful vision.

Detection of light serves many tasks. Independent of form vision, the detection of brightness (irradiance) is used to regulate pupil size,1 entrain circadian rhythms to the day-night cycle,2 and modulate endocrine function.3 Irradiance information is transmitted to central nuclei by a specialized subset of intrinsically photosensitive retinal ganglion cells (ipRGCs).4,5 The response of ipRGCs to light is a composite of their intrinsic melanopsin-generated activity and rod-cone photoreceptor-dependent activation mediated by interneurons of the inner retina.6 However, morphologic and functional specialization among ipRGCs has been identified, and these “ipRGC types” show variation in their projections to central nuclei.7–10 How these differences in ipRGC form, function, and central projections relate to a given irradiance response is not well understood. For instance, the pupillary light reflex and negative masking (a suppression of activity by light) both respond to “lights on” in an irradiance-dependent manner.1,11 However, the effect of outer retina degeneration differs dramatically between these irradiance responses, with a paradoxical enhancement of irradiance sensitivity in negative masking12 and a severe loss of sensitivity in the pupillary light reflex.1,13,14 At the level of the retina, such phenotypic variability could arise from secondary effects of outer retina disease on ipRGCs or from differences in rod-cone input to the different ipRGC types. Although inner retinal circuitry is diverse, all vertical transmission of rod and cone signals to ganglion cells is, at some point, mediated by bipolar cells (BCs).15 Therefore, differences between responses could arise from specificity in bipolar cells mediating rod-cone input. The aim of this study was to determine whether there are differences in inner retinal pathways mediating rod-cone input to functionally distinct irradiance responses and whether such differences could contribute to the divergent effects of outer retinal disease on the different irradiance responses. Negative masking and pupillary light reflex were compared between mice with intact inner-retinal circuitry (wild-type), mice selectively lacking the ON-BC pathway of rod-cone input (Nob4), and mice with degenerate rods and cones (rd1), effectively lacking input to both ON- and OFF-BCs (Fig. 1). Figure 1. Vertical transmission of rod-cone input to ganglion cells. Green: ON pathways. Blue: OFF pathways. Loss of function is indicated by gray shading or cell absence. (A) When rods and cones respond to light, metabotropic or ON-BCs depolarize, and ionotropic ...