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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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Masking response in Opa1+/+ and Opa1+/− mice.(A) The average wheel running revolutions on the night (gray background) of the 3 h light pulse (white background) are plotted relative to the baseline levels (the night before the pulse) for Opa1+/+ (n = 6) and Opa1+/− (n = 7) mice. The masking pulse completely suppressed activity in both genotypes immediately. ANOVA analysis found no significant effect of genotype on the baseline corrected activity levels (p = 0.468) (B) Hourly breakdown of activity during the masking pulse. A 2-way ANOVA using activity in each hour of light pulse and genotype as factors found a significant effect of hour of light pulse (p<0.005) but no significant effect of genotype (p = 0.143) and no interaction between genotype and light pulse hour (p = 0.359). All data are presented as mean ± SEM.
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pone-0056350-g002: Masking response in Opa1+/+ and Opa1+/− mice.(A) The average wheel running revolutions on the night (gray background) of the 3 h light pulse (white background) are plotted relative to the baseline levels (the night before the pulse) for Opa1+/+ (n = 6) and Opa1+/− (n = 7) mice. The masking pulse completely suppressed activity in both genotypes immediately. ANOVA analysis found no significant effect of genotype on the baseline corrected activity levels (p = 0.468) (B) Hourly breakdown of activity during the masking pulse. A 2-way ANOVA using activity in each hour of light pulse and genotype as factors found a significant effect of hour of light pulse (p<0.005) but no significant effect of genotype (p = 0.143) and no interaction between genotype and light pulse hour (p = 0.359). All data are presented as mean ± SEM.

Mentions: Previous studies have shown that light of ∼200 lux presented at night induced a complete negative masking response in wildtype mice[29] and in rodless/coneless mice[30] whereas negative masking was significantly impaired in melanopsin knockout mice[22]. We examined masking responses to 200 lux stimuli at ZT14 in Opa1+/+and Opa1+/− mice. Both genotypes significantly decreased their activity during the 3 h light exposure (data normalised to baseline from previous night; Figure 2A). Opa1+/+and Opa1+/− mice acutely stopped running during the first hour of the light pulse and activity levels subsequently increased, as has been previously shown in wildtype strains[22]. The baseline corrected activity levels during the light pulse was not significantly different between genotypes. An hourly breakdown of the number of wheel revolutions during the light pulse also showed no significant difference between genotypes (Figure 2B).


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)

Masking response in Opa1+/+ and Opa1+/− mice.(A) The average wheel running revolutions on the night (gray background) of the 3 h light pulse (white background) are plotted relative to the baseline levels (the night before the pulse) for Opa1+/+ (n = 6) and Opa1+/− (n = 7) mice. The masking pulse completely suppressed activity in both genotypes immediately. ANOVA analysis found no significant effect of genotype on the baseline corrected activity levels (p = 0.468) (B) Hourly breakdown of activity during the masking pulse. A 2-way ANOVA using activity in each hour of light pulse and genotype as factors found a significant effect of hour of light pulse (p<0.005) but no significant effect of genotype (p = 0.143) and no interaction between genotype and light pulse hour (p = 0.359). All data are presented as mean ± SEM.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3569441&req=5

pone-0056350-g002: Masking response in Opa1+/+ and Opa1+/− mice.(A) The average wheel running revolutions on the night (gray background) of the 3 h light pulse (white background) are plotted relative to the baseline levels (the night before the pulse) for Opa1+/+ (n = 6) and Opa1+/− (n = 7) mice. The masking pulse completely suppressed activity in both genotypes immediately. ANOVA analysis found no significant effect of genotype on the baseline corrected activity levels (p = 0.468) (B) Hourly breakdown of activity during the masking pulse. A 2-way ANOVA using activity in each hour of light pulse and genotype as factors found a significant effect of hour of light pulse (p<0.005) but no significant effect of genotype (p = 0.143) and no interaction between genotype and light pulse hour (p = 0.359). All data are presented as mean ± SEM.
Mentions: Previous studies have shown that light of ∼200 lux presented at night induced a complete negative masking response in wildtype mice[29] and in rodless/coneless mice[30] whereas negative masking was significantly impaired in melanopsin knockout mice[22]. We examined masking responses to 200 lux stimuli at ZT14 in Opa1+/+and Opa1+/− mice. Both genotypes significantly decreased their activity during the 3 h light exposure (data normalised to baseline from previous night; Figure 2A). Opa1+/+and Opa1+/− mice acutely stopped running during the first hour of the light pulse and activity levels subsequently increased, as has been previously shown in wildtype strains[22]. The baseline corrected activity levels during the light pulse was not significantly different between genotypes. An hourly breakdown of the number of wheel revolutions during the light pulse also showed no significant difference between genotypes (Figure 2B).

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