title: Non-image-forming light driven functions are preserved in a mouse model of autosomal dominant optic atrophy.
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.
authors: Nuffield Department of Clinical Neurosciences, Nuffield Laboratory of Ophthalmology, University of Oxford, Oxford, United Kingdom.
authors: Georgia
authors: G
authors: Perganta
authors: Alun R
authors: AR
authors: Barnard
authors: Christiana
authors: C
authors: Katti
authors: Athanasios
authors: A
authors: Vachtsevanos
authors: Ron H
authors: RH
authors: Douglas
authors: Robert E
authors: RE
authors: MacLaren
authors: Marcela
authors: M
authors: Votruba
authors: Sumathi
authors: S
authors: Sekaran
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000528:radiation effects; D002940:Circadian Rhythm / Q000528:radiation effects; D003624:Darkness; D004195:Disease Models, Animal; D020558:GTP Phosphohydrolases / Q000172:deficiency / Q000235:genetics; D005786:Gene Expression Regulation / Q000528:radiation effects; D008027:Light; D008297:Male; D051379:Mice; D009154:Mutation; D029241:Optic Atrophy, Autosomal Dominant / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D011680:Pupil / Q000528:radiation effects; D012165:Retinal Ganglion Cells / Q000378:metabolism / Q000528:radiation effects; D017299:Rod Opsins / Q000378:metabolism; D012890:Sleep / Q000502:physiology / Q000528:radiation effects; D000099210:Melanopsin
chemical_list: D020558:GTP Phosphohydrolases; D017299:Rod Opsins; D000099210:Melanopsin; C498809:Opa1 protein, mouse