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Non-image-forming light driven functions are preserved in a mouse model of autosomal dominant optic atrophy.

Perganta G, Barnard AR, Katti C, Vachtsevanos A, Douglas RH, MacLaren RE, Votruba M, Sekaran S - PLoS ONE (2013)

Bottom Line: There were no significant differences in any parameter tested relative to wildtype littermate controls.Furthermore, there was no significant difference in the number of melanopsin-expressing RGCs, cell morphology or melanopsin transcript levels between genotypes.The results provide support to growing evidence that the melanopsin-expressing RGCs are protected in mitochondrial optic neuropathies.

View Article: PubMed Central - PubMed

Affiliation: Nuffield Department of Clinical Neurosciences, Nuffield Laboratory of Ophthalmology, University of Oxford, Oxford, United Kingdom.

ABSTRACT
Autosomal dominant optic atrophy (ADOA) is a slowly progressive optic neuropathy that has been associated with mutations of the OPA1 gene. In patients, the disease primarily affects the retinal ganglion cells (RGCs) and causes optic nerve atrophy and visual loss. A subset of RGCs are intrinsically photosensitive, express the photopigment melanopsin and drive non-image-forming (NIF) visual functions including light driven circadian and sleep behaviours and the pupil light reflex. Given the RGC pathology in ADOA, disruption of NIF functions might be predicted. Interestingly in ADOA patients the pupil light reflex was preserved, although NIF behavioural outputs were not examined. The B6; C3-Opa1(Q285STOP) mouse model of ADOA displays optic nerve abnormalities, RGC dendropathy and functional visual disruption. We performed a comprehensive assessment of light driven NIF functions in this mouse model using wheel running activity monitoring, videotracking and pupillometry. Opa1 mutant mice entrained their activity rhythm to the external light/dark cycle, suppressed their activity in response to acute light exposure at night, generated circadian phase shift responses to 480 nm and 525 nm pulses, demonstrated immobility-defined sleep induction following exposure to a brief light pulse at night and exhibited an intensity dependent pupil light reflex. There were no significant differences in any parameter tested relative to wildtype littermate controls. Furthermore, there was no significant difference in the number of melanopsin-expressing RGCs, cell morphology or melanopsin transcript levels between genotypes. Taken together, these findings suggest the preservation of NIF functions in Opa1 mutants. The results provide support to growing evidence that the melanopsin-expressing RGCs are protected in mitochondrial optic neuropathies.

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Related in: MedlinePlus

Pupil light reflex in Opa1+/+ and Opa1+/− mice.The average minimum pupil area expressed as a percentage of maximum dilation following illumination with various intensities of white light for Opa1+/+ (n = 5) and Opa1+/− (n = 5) mice. All data are fitted with four term sigmoidal functions (solid lines) of the form y = y0+a/(1+exp(-(x-x0)/b)) (goodness of fit of fitted curve to actual data (R2): Opa1+/+ = 0.993 and Opa1+/− = 0.995). A 2-way ANOVA using intensity and genotype as factors showed a significant effect of light intensity (p<0.0001) but no significant effect of genotype (p = 0.51) and no significant interaction between genotype and intensity (p = 0.99).
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pone-0056350-g005: Pupil light reflex in Opa1+/+ and Opa1+/− mice.The average minimum pupil area expressed as a percentage of maximum dilation following illumination with various intensities of white light for Opa1+/+ (n = 5) and Opa1+/− (n = 5) mice. All data are fitted with four term sigmoidal functions (solid lines) of the form y = y0+a/(1+exp(-(x-x0)/b)) (goodness of fit of fitted curve to actual data (R2): Opa1+/+ = 0.993 and Opa1+/− = 0.995). A 2-way ANOVA using intensity and genotype as factors showed a significant effect of light intensity (p<0.0001) but no significant effect of genotype (p = 0.51) and no significant interaction between genotype and intensity (p = 0.99).

Mentions: Melanopsin-expressing and conventional RGCs contribute to the PLR [16], [17], [24], [34]. Both wildtype and Opa1 mutant mice demonstrated a graded pupil constriction in response to increasing illumination across a full intensity range. The average irradiance response curve for Opa1+/− mice was very similar to that of wildtype littermates (Figure 5). A 2-way ANOVA using intensity and genotype as factors showed a significant effect of light intensity (p<0.0001) but no significant effect of genotype (p = 0.51) and no significant interaction between genotype and intensity (p = 0.99).


Non-image-forming light driven functions are preserved in a mouse model of autosomal dominant optic atrophy.

Perganta G, Barnard AR, Katti C, Vachtsevanos A, Douglas RH, MacLaren RE, Votruba M, Sekaran S - PLoS ONE (2013)

Pupil light reflex in Opa1+/+ and Opa1+/− mice.The average minimum pupil area expressed as a percentage of maximum dilation following illumination with various intensities of white light for Opa1+/+ (n = 5) and Opa1+/− (n = 5) mice. All data are fitted with four term sigmoidal functions (solid lines) of the form y = y0+a/(1+exp(-(x-x0)/b)) (goodness of fit of fitted curve to actual data (R2): Opa1+/+ = 0.993 and Opa1+/− = 0.995). A 2-way ANOVA using intensity and genotype as factors showed a significant effect of light intensity (p<0.0001) but no significant effect of genotype (p = 0.51) and no significant interaction between genotype and intensity (p = 0.99).
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3569441&req=5

pone-0056350-g005: Pupil light reflex in Opa1+/+ and Opa1+/− mice.The average minimum pupil area expressed as a percentage of maximum dilation following illumination with various intensities of white light for Opa1+/+ (n = 5) and Opa1+/− (n = 5) mice. All data are fitted with four term sigmoidal functions (solid lines) of the form y = y0+a/(1+exp(-(x-x0)/b)) (goodness of fit of fitted curve to actual data (R2): Opa1+/+ = 0.993 and Opa1+/− = 0.995). A 2-way ANOVA using intensity and genotype as factors showed a significant effect of light intensity (p<0.0001) but no significant effect of genotype (p = 0.51) and no significant interaction between genotype and intensity (p = 0.99).
Mentions: Melanopsin-expressing and conventional RGCs contribute to the PLR [16], [17], [24], [34]. Both wildtype and Opa1 mutant mice demonstrated a graded pupil constriction in response to increasing illumination across a full intensity range. The average irradiance response curve for Opa1+/− mice was very similar to that of wildtype littermates (Figure 5). A 2-way ANOVA using intensity and genotype as factors showed a significant effect of light intensity (p<0.0001) but no significant effect of genotype (p = 0.51) and no significant interaction between genotype and intensity (p = 0.99).

Bottom Line: There were no significant differences in any parameter tested relative to wildtype littermate controls.Furthermore, there was no significant difference in the number of melanopsin-expressing RGCs, cell morphology or melanopsin transcript levels between genotypes.The results provide support to growing evidence that the melanopsin-expressing RGCs are protected in mitochondrial optic neuropathies.

View Article: PubMed Central - PubMed

Affiliation: Nuffield Department of Clinical Neurosciences, Nuffield Laboratory of Ophthalmology, University of Oxford, Oxford, United Kingdom.

ABSTRACT
Autosomal dominant optic atrophy (ADOA) is a slowly progressive optic neuropathy that has been associated with mutations of the OPA1 gene. In patients, the disease primarily affects the retinal ganglion cells (RGCs) and causes optic nerve atrophy and visual loss. A subset of RGCs are intrinsically photosensitive, express the photopigment melanopsin and drive non-image-forming (NIF) visual functions including light driven circadian and sleep behaviours and the pupil light reflex. Given the RGC pathology in ADOA, disruption of NIF functions might be predicted. Interestingly in ADOA patients the pupil light reflex was preserved, although NIF behavioural outputs were not examined. The B6; C3-Opa1(Q285STOP) mouse model of ADOA displays optic nerve abnormalities, RGC dendropathy and functional visual disruption. We performed a comprehensive assessment of light driven NIF functions in this mouse model using wheel running activity monitoring, videotracking and pupillometry. Opa1 mutant mice entrained their activity rhythm to the external light/dark cycle, suppressed their activity in response to acute light exposure at night, generated circadian phase shift responses to 480 nm and 525 nm pulses, demonstrated immobility-defined sleep induction following exposure to a brief light pulse at night and exhibited an intensity dependent pupil light reflex. There were no significant differences in any parameter tested relative to wildtype littermate controls. Furthermore, there was no significant difference in the number of melanopsin-expressing RGCs, cell morphology or melanopsin transcript levels between genotypes. Taken together, these findings suggest the preservation of NIF functions in Opa1 mutants. The results provide support to growing evidence that the melanopsin-expressing RGCs are protected in mitochondrial optic neuropathies.

Show MeSH
Related in: MedlinePlus