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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

Phase shift behaviour in Opa1+/+ and Opa1+/− mice.Representative actograms from (A) Opa1+/+ and (B) Opa1+/− mice in constant dark (DD) conditions. Animals were exposed to 15 min light pulses every ∼15 days. Photon matched pulses at 480 nm (black arrow) or 525 nm (white arrow; 1×1011 photons/s/cm2) were applied at CT16. Animals were also exposed to a dark sham pulse condition (grey arrow). (C) The size of the phase shift response are plotted for the 525 nm, 480 nm and sham conditions for Opa1+/+ (n = 6) and Opa1+/− (n = 7) mice. A two-way ANOVA with genotype and wavelength as factors was performed. There was no significant effect of wavelength (p = 0.66) or genotype (p = 0.17) and the interaction of genotype and wavelength was not significant (p = 0.91).
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pone-0056350-g003: Phase shift behaviour in Opa1+/+ and Opa1+/− mice.Representative actograms from (A) Opa1+/+ and (B) Opa1+/− mice in constant dark (DD) conditions. Animals were exposed to 15 min light pulses every ∼15 days. Photon matched pulses at 480 nm (black arrow) or 525 nm (white arrow; 1×1011 photons/s/cm2) were applied at CT16. Animals were also exposed to a dark sham pulse condition (grey arrow). (C) The size of the phase shift response are plotted for the 525 nm, 480 nm and sham conditions for Opa1+/+ (n = 6) and Opa1+/− (n = 7) mice. A two-way ANOVA with genotype and wavelength as factors was performed. There was no significant effect of wavelength (p = 0.66) or genotype (p = 0.17) and the interaction of genotype and wavelength was not significant (p = 0.91).

Mentions: Light pulses of two different wavelengths were applied at CT16 to elicit phase shift behaviour. 480 nm light was applied to maximally stimulate the melanopsin-RGCs (λmax∼480 nm) and a 525 nm pulse was used to maximally stimulate the MW-sensitive cone (λmax∼508 nm) input to the melanopsin RGCs. The 480 nm pulse induced a delay in the phase of activity onset in both Opa1+/+ and Opa1+/− mice (Figure 3A,B). The average magnitude of the phase shifts was not significantly different between genotypes (Figure 3C). In both genotypes, the period of the activity rhythm was not altered following the light pulse (τ after 480 nm pulse: Opa1+/+ 23.6±0.09 h; Opa1+/− 23.6±0.07 h). The pulse of 525 nm also successfully induced a phase delay in activity onset in Opa1+/+ and Opa1+/− mice (Figure 3A,B). There was no significant difference in the size of the phase shifts between genotypes (Figure 3C). Again the period length was not altered after the light pulse for each genotype (τ after 525 nm pulse: Opa1+/+ 23.6±0.09 h; Opa1+/− 23.6±0.06 h). Importantly in a control sham pulse exposure, no obvious phase shift was observed in either wildtype or heterozygous animals (Figure 3C).


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)

Phase shift behaviour in Opa1+/+ and Opa1+/− mice.Representative actograms from (A) Opa1+/+ and (B) Opa1+/− mice in constant dark (DD) conditions. Animals were exposed to 15 min light pulses every ∼15 days. Photon matched pulses at 480 nm (black arrow) or 525 nm (white arrow; 1×1011 photons/s/cm2) were applied at CT16. Animals were also exposed to a dark sham pulse condition (grey arrow). (C) The size of the phase shift response are plotted for the 525 nm, 480 nm and sham conditions for Opa1+/+ (n = 6) and Opa1+/− (n = 7) mice. A two-way ANOVA with genotype and wavelength as factors was performed. There was no significant effect of wavelength (p = 0.66) or genotype (p = 0.17) and the interaction of genotype and wavelength was not significant (p = 0.91).
© Copyright Policy
Related In: Results  -  Collection

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

pone-0056350-g003: Phase shift behaviour in Opa1+/+ and Opa1+/− mice.Representative actograms from (A) Opa1+/+ and (B) Opa1+/− mice in constant dark (DD) conditions. Animals were exposed to 15 min light pulses every ∼15 days. Photon matched pulses at 480 nm (black arrow) or 525 nm (white arrow; 1×1011 photons/s/cm2) were applied at CT16. Animals were also exposed to a dark sham pulse condition (grey arrow). (C) The size of the phase shift response are plotted for the 525 nm, 480 nm and sham conditions for Opa1+/+ (n = 6) and Opa1+/− (n = 7) mice. A two-way ANOVA with genotype and wavelength as factors was performed. There was no significant effect of wavelength (p = 0.66) or genotype (p = 0.17) and the interaction of genotype and wavelength was not significant (p = 0.91).
Mentions: Light pulses of two different wavelengths were applied at CT16 to elicit phase shift behaviour. 480 nm light was applied to maximally stimulate the melanopsin-RGCs (λmax∼480 nm) and a 525 nm pulse was used to maximally stimulate the MW-sensitive cone (λmax∼508 nm) input to the melanopsin RGCs. The 480 nm pulse induced a delay in the phase of activity onset in both Opa1+/+ and Opa1+/− mice (Figure 3A,B). The average magnitude of the phase shifts was not significantly different between genotypes (Figure 3C). In both genotypes, the period of the activity rhythm was not altered following the light pulse (τ after 480 nm pulse: Opa1+/+ 23.6±0.09 h; Opa1+/− 23.6±0.07 h). The pulse of 525 nm also successfully induced a phase delay in activity onset in Opa1+/+ and Opa1+/− mice (Figure 3A,B). There was no significant difference in the size of the phase shifts between genotypes (Figure 3C). Again the period length was not altered after the light pulse for each genotype (τ after 525 nm pulse: Opa1+/+ 23.6±0.09 h; Opa1+/− 23.6±0.06 h). Importantly in a control sham pulse exposure, no obvious phase shift was observed in either wildtype or heterozygous animals (Figure 3C).

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