title: Opa1 deficiency in a mouse model of dominant optic atrophy leads to retinal ganglion cell dendropathy.
abstract: The heterozygous mutation B6;C3-Opa1(Q285STOP), which models autosomal dominant optic atrophy, leads to a 50% reduction in Opa1 transcript and protein in the mouse retina and neural tissues and is associated with visual dysfunction and structural changes in the murine retina and optic nerve. In this article we use this model to quantify and evaluate the dendritic morphology of retinal ganglion cells. Retinal ganglion cells in Opa1(+/-) mutant mice (n=16) and accompanying age- and sex-matched controls (n=11) (age ranges of <10, 10-15 and >20 months) were labelled DiOlistically with carbocyanine dyes to quantify changes in dendritic tree architecture as a function of age. We observed localized dendritic reduction to sublamina b of the inner plexiform layer without retinal ganglion cell loss, showing dendritic pruning of on- but not off-centre retinal ganglion cells, and this effect was exacerbated with age. The mean dendritic field area was reduced in on-centre retinal ganglion cells of 10- to 15-month-old mice (-24.24%; C(V) =0.68; P<0.05) and >20-month-old mice (-43.22%; C(V) =0.75; P<0.05) compared with age-matched wild-type controls. Similar changes were seen in average total dendritic length in on-centre retinal ganglion cells of 10- to 15-month-old mice (-31.66%; C(V) =0.67; P<0.05) and >20-month-old mice (-49.55%; C(V) =0.63; P<0.05). Sholl analysis showed a marked difference in the dendritic arborization of on-centre retinal ganglion cells in the 10- to 15-month-old group (area under the curve -21.67%; P>0.05) and of the >20-month-old group (area under the curve -42.12%; P<0.05) compared with the control group. There was no detectable change in dendritic morphology in <10-month-old Opa1(+/-) mutant mice compared with wild-type (P>0.05). No significant changes (P>0.05) were seen in off-centre retinal ganglion cells. Finally, there was also no significant change (P>0.05) in the retinal ganglion cell count across all age groups. In conclusion, we show dendritic pruning in on-centre retinal ganglion cells of the Opa1(+/-) mouse model of autosomal dominant optic atrophy from as early as 10 months of age. These results highlight the importance of normal mitochondrial fusion balance, as influenced by the OPA1 protein in maintaining the dendritic morphology of retinal ganglion cells. Dendritic pruning precedes the onset of clinical visual loss and structural changes in the optic nerve in the absence of significant cell loss.
authors.affiliation: School of Optometry Vision Sciences, Maindy Road, Cardiff University, Cardiff, UK.
authors.forename: Pete A
authors.initials: PA
authors.lastname: Williams
authors.forename: James E
authors.initials: JE
authors.lastname: Morgan
authors.forename: Marcela
authors.initials: M
authors.lastname: Votruba
mesh_terms: D000818:Animals; D001284:Atrophy / Q000378:metabolism / Q000473:pathology; D002452:Cell Count; D003712:Dendrites / Q000378:metabolism / Q000473:pathology*; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D029241:Optic Atrophy, Autosomal Dominant / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D012165:Retinal Ganglion Cells / Q000378:metabolism / Q000473:pathology*
chemical_list: D020558:GTP Phosphohydrolases; C498809:Opa1 protein, mouse