In previous electrophysiological experiments from hypopigmented animals (mice, rats, rabbits), single-unit recordings from both retinal ganglion axons and cells in the superior colliculus have demonstrated an increase in threshold in the dark-adapted state which is roughly proportional to the animal's ocular melanin concentration. We have examined the thresholds in hypopigmented mice by using a behavioral water maze screening test and found similar threshold elevations to the electrophysiology. In the present study, we investigated the contribution of retinal light damage to the threshold elevation in an albino mouse strain which is relatively resistant to light damage (C57BL/6J c2J/c2J) and mice with profound retinal degeneration (C57BL/6J rd/rd).

Black or albino littermates (C57BL/6J + / c2J or c2J / c2J) were placed in either constant light (350 cd/m2) or dim cycling light (0.001 cd/m2) for 21 days before testing. The normally pigmented animals had thresholds of 1.00 × 10−5 cd/m2 regardless of their light history. The albino mice (c2J/c2J) maintained in constant light had a slight 0.30 log unit elevation compared to their controls that were maintained in dim cycling light 6.3 × 10−4 cd/m2 (similar to previously published reports).

We examined the retinal morphology of representative animals in semi-thin plastic sections. We could not detect any light damage (overall morphology or cell counts in the outer-nuclear layer) in either the normally pigmented animals or the albino mice (c2J/c2J) maintained in dim cycling light. We found extensive light damage in the albino mice (c2J/c2J) maintained in constant light (virtual absence of photoreceptor outersegments) that corresponded to the slight elevation in threshold. We conclude that the elevation in threshold found in albino mice (c2J/c2J) maintained in dim cycling light is not the result of light damage. These results support our previous findings that the sensitivity defect in hypopigmented animals is proportional to the degree of ocular hypopigmentation.

Significant variation in absolute dark-adapted thresholds is observed both within and between strains of mice with differing ocular pigmentation levels. Differences in threshold within a single strain are related to the Williams' photostasis effect, that is, photoreceptor rhodopsin levels are dependent upon ambient lighting conditions. To examine threshold differences among strains, we equalized rhodopsin levels by maintaining albino mice (c2J/c2J) at 2 × 10−4 cd/m2 (dim light) and black mice at 2 × 102 cd/m2 (bright light). This resulted in ocular rhodopsin levels for albino mice (albino—dim) of 494 ± 11 pmoles/eye and rhodopsin levels for black mice (black—bright) of 506 ± 25 pmoles/eye. For comparison, rhodopsin levels in black mice maintained in dim light are 586 ± 46 pmoles/eye and 217 ± 46 pmoles/eye in albino mice maintained in bright light. We found similar dark-adapted thresholds (6.38 log cd/m2vs. 6.47 log cd/m2)) in albino and black mice with equivalent rhodopsin determined with a water maze test. This suggests that dark-adapted thresholds are directly related to rhodopsin levels regardless of the level of ocular melanin. The number of photoreceptors, photoreceptor layer thickness, and outer segment length did not differ significantly between albino (dark) and black mice (bright). These results demonstrate that the visual sensitivity defect found in hypopigmented animals is secondary to abnormal rhodopsin regulation and that hypopigmented animals have either an improper input to the photostasis mechanism or that the photostasis mechanism is defective.

Vitiligo is a depigmenting disorder characterised by the loss of melanocytes from the cutaneous epidermis. Although the exact aetiology of vitiligo has not yet been established, the abnormal immune responses frequently observed in vitiligo patients have led to the suggestion that, in some cases, the condition has an autoimmune component. Briefly, circulating autoantibodies and autoreactive T cells that recognise pigment cell antigens have been detected in the sera of a significant proportion of vitiligo patients compared with healthy individuals. In addition, vitiligo is often associated with other disorders that have an autoimmune origin, including Hashimoto's thyroiditis, Graves' disease, type 1 insulin-dependent diabetes mellitus and Addison's disease. Furthermore, effective use of immunosuppressive therapies to treat vitiligo, the association of vitiligo with certain major histocompatibility complex antigens, and evidence from animal models of the disease have all added credence to the hypothesis that immune reactions play a role in vitiligo pathogenesis. This review presents and discusses the evidence for immunological pathomechanisms in vitiligo.

Previous work suggests that photoreceptor synaptic ribbon length and absolute dark-adapted threshold may vary during a 24-h diurnal cycle. To test this hypothesis, we examined the length of photoreceptor synaptic ribbons and the dark-adapted threshold in black (+/+) and albino (c2J/c2J) C57BL/6J mice at six times over a 24-h period. Testing began 2 h after light onset (ZT 2:00) and continued at successive 4-h intervals (12 h:12 h light:dark). We determined the length of the synaptic ribbons in frozen sections by labeling them with an antibody specific for synaptic ribbons. Synaptic ribbons vary in length at different points in the diurnal cycle in both types of mice, but the synaptic ribbons in black mice are longer than those in albino mice by an average of 0.33 μm. The synaptic ribbons of black mice also have a larger response to changes in the light cycle. Ribbon length in black mice ranges from 1.66 μm to 1.4 μm, whereas ribbon length in albino mice ranges from 1.32 μm to 1.25 μm. The shortest ribbons are evident 6 h after light onset in both types of mice, whereas the longest ribbons appear within 2 h after light onset. These changes in synaptic ribbon length support the idea that photoreceptor synaptic ribbons are dynamic structures whose length changes over a 24-h diurnal cycle. Examining black and albino mice with a water-maze behavioral assay showed that visual thresholds in black and albino mice vary over the 24-h diurnal cycle. The visual thresholds of albino mice are elevated compared with black mice at all times tested. This is consistent with previous findings of visual thresholds in hypopigmented mice. The lowest threshold (greatest sensitivity) is present 2 h after light onset (ZT 2:00) and corresponds to the time when synaptic ribbons are the longest. The highest threshold is observed 6 h after light onset, the time when synaptic ribbons are shortest. These results show that synaptic ribbon length and visual sensitivity vary together in relation to the time.

Controversy over the relationship between ocular pigmentation and absolute dark-adapted light sensitivity has persisted for over two decades. Previous electrophysiological experiments in hypopigmented mammals (mice, rats, rabbits) show increased thresholds in the dark-adapted state proportional to the deficit in ocular melanin. Animals with the least amount of ocular melanin have the most elevated thresholds. Dark-adapted thresholds in hypopigmented mice show similar threshold elevations in behavioral tests. The present study extends these findings to show that a specific increase in ocular pigmentation results in the converse effect, lowered absolute dark-adapted thresholds. The increase in ocular melanin was accomplished by keeping Himalayan mice in the cold (4°C) for 6 weeks. Himalayan mice (C57BL/6J cH/cH) were compared to black mice (C57BL/6J +/+) and albino mice (C57BL/6J c2J/c2J) after 6 weeks at either 4°C or 20°C in 12-h cycling light (<1 cd/m2). The Himalayan mice that were kept in the cold exhibited a 44% increase in ocular melanin compared to Himalayan mice kept at room temperature. Cold rearing did not effect ocular melanin or visual thresholds in control animals (black mice = 10−5.9 cd/m2 and albino mice = 10−4.4 cd/m2). In contrast, the Himalayan mice maintained at 4°C had thresholds of 10−5.7 cd/m2 compared to 10−5.1 cd/m2 for Himalayan mice kept at 20°C. This represents compelling evidence of a direct relationship between ocular melanin concentration and absolute dark-adapted light sensitivity.