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.
Highlights
Autosomal dominant optic atrophy (ADOA) is the most common form of inherited optic neuropathy[1,2,3]
Abnormalities in the axons and dendritic arbors of retinal ganglion cells (RGCs) in the B6; C3-Opa1Q285STOP mouse model of ADOA[8,10] are believed to underlie functional visual dysfunction which begins to be apparent by 12 months of age [8,12,35]
Despite the pathophysiology of the RGC population, we have found that photic regulation of circadian activity, immobility-defined sleep behaviour and the pupil light reflex is preserved in Opa1 mutant mice
Summary
Autosomal dominant optic atrophy (ADOA) is the most common form of inherited optic neuropathy[1,2,3]. It is clinically characterized by a moderate to severe decrease in visual acuity, central visual field deficits, colour vision defects and temporal or diffuse optic nerve pallor[1,3,4]. In the B6; C3-Opa1Q285STOP model, abnormalities in the optic nerve were detected by 9 months[8] without significant RGC loss[10]. A specific deficit in the photopic negative response of the electroretinogram which reflects ganglion cell function, was detected in Opa mutants from 12 months[12]. A reduction in visual acuity detectable by optokinetic drum screening was described[8]
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