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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

Circadian behaviour in Opa1+/+ and Opa1+/− mice.Representative actograms from (A) Opa1+/+ and (B) Opa1+/− mice entrained to a 12/12 LD cycle and subsequently released into constant darkness (DD). Each horizontal line corresponds to one day and the data has been double plotted. The black vertical bars represent activity (i.e. wheel revolutions). The shaded region represents lights ON. (C) Table showing average period (τ), total activity levels and length of the active phase in LD and in DD for Opa1+/+ (n = 6) and Opa1+/− (n = 7) mice. There were no significant differences between genotypes (unpaired students t-test; p values are shown). All data are presented as mean ± SEM.
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pone-0056350-g001: Circadian behaviour in Opa1+/+ and Opa1+/− mice.Representative actograms from (A) Opa1+/+ and (B) Opa1+/− mice entrained to a 12/12 LD cycle and subsequently released into constant darkness (DD). Each horizontal line corresponds to one day and the data has been double plotted. The black vertical bars represent activity (i.e. wheel revolutions). The shaded region represents lights ON. (C) Table showing average period (τ), total activity levels and length of the active phase in LD and in DD for Opa1+/+ (n = 6) and Opa1+/− (n = 7) mice. There were no significant differences between genotypes (unpaired students t-test; p values are shown). All data are presented as mean ± SEM.

Mentions: Circadian photoentrainment is driven by both melanopsin and conventional RGC pathways [16], [17], [18]. The ability of Opa1+/− and Opa1+/+ mice to entrain to a 12∶12 LD cycle was assessed (Figure 1A,B). Both genotypes largely confined their activity to the dark phase suggesting the animals were entrained to the normal LD cycle. The period length (τ) and length of the active phase were equivalent for wildtype and heterozygous mice (Figure 1C). Total activity (average number of wheel revolutions per day) was slightly higher in Opa1+/− animals relative to the wildtype controls but this difference was not significant (Figure 1C). When released into constant darkness (DD), the phase of activity onset for the first day in DD was coincident with lights OFF of the previous LD cycle for both genotypes (Figure 1A,B) again suggesting that the mice were entrained to the light signal.


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)

Circadian behaviour in Opa1+/+ and Opa1+/− mice.Representative actograms from (A) Opa1+/+ and (B) Opa1+/− mice entrained to a 12/12 LD cycle and subsequently released into constant darkness (DD). Each horizontal line corresponds to one day and the data has been double plotted. The black vertical bars represent activity (i.e. wheel revolutions). The shaded region represents lights ON. (C) Table showing average period (τ), total activity levels and length of the active phase in LD and in DD for Opa1+/+ (n = 6) and Opa1+/− (n = 7) mice. There were no significant differences between genotypes (unpaired students t-test; p values are shown). All data are presented as mean ± SEM.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0056350-g001: Circadian behaviour in Opa1+/+ and Opa1+/− mice.Representative actograms from (A) Opa1+/+ and (B) Opa1+/− mice entrained to a 12/12 LD cycle and subsequently released into constant darkness (DD). Each horizontal line corresponds to one day and the data has been double plotted. The black vertical bars represent activity (i.e. wheel revolutions). The shaded region represents lights ON. (C) Table showing average period (τ), total activity levels and length of the active phase in LD and in DD for Opa1+/+ (n = 6) and Opa1+/− (n = 7) mice. There were no significant differences between genotypes (unpaired students t-test; p values are shown). All data are presented as mean ± SEM.
Mentions: Circadian photoentrainment is driven by both melanopsin and conventional RGC pathways [16], [17], [18]. The ability of Opa1+/− and Opa1+/+ mice to entrain to a 12∶12 LD cycle was assessed (Figure 1A,B). Both genotypes largely confined their activity to the dark phase suggesting the animals were entrained to the normal LD cycle. The period length (τ) and length of the active phase were equivalent for wildtype and heterozygous mice (Figure 1C). Total activity (average number of wheel revolutions per day) was slightly higher in Opa1+/− animals relative to the wildtype controls but this difference was not significant (Figure 1C). When released into constant darkness (DD), the phase of activity onset for the first day in DD was coincident with lights OFF of the previous LD cycle for both genotypes (Figure 1A,B) again suggesting that the mice were entrained to the light signal.

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