title: Electrophysiological and histologic assessment of retinal ganglion cell fate in a mouse model for OPA1-associated autosomal dominant optic atrophy.
abstract: OBJECTIVE
  The main disease features of autosomal dominant optic atrophy (ADOA) are a bilateral reduction of visual acuity, cecocentral scotoma, and frequently tritanopia, which have been ascribed to a progressive loss of retinal ganglion cells (RGCs) and subsequent degeneration of the optic nerve. The main disease-causing gene is OPA1. Here, we examine a mouse carrying a pathogenic mutation in Opa1 by electrophysiological measurements and assess the fate of RGCs.
  
  
  METHODS
  Two-year-old animals underwent a full examination by electroretinography (ERG) and visually evoked potential (VEP) measurements to assess the function of the outer and inner retina and the optic nerve. Retrograde Fluorogold labeling was performed to determine the number of surviving RGCs and to assess axonal transport by neurofilament counterstaining. Phagocytosis-dependent labeled microglial cells were identified by an Iba-1 staining.
  
  
  RESULTS
  ERG responses were normal in aged Opa1 mice. VEP measurements revealed significantly reduced amplitudes but no change in the latencies in contrast to extended latencies found in glaucoma. Retrograde labeling of RGCs showed a significant reduction in the number of RGCs in Opa1 mice. Long-term experiments revealed the presence of microglial cells with ingested fluorescent dye.
  
  
  CONCLUSIONS
  This is the first electrophysiological demonstration of a visual function deficit in aged Opa1 mice. VEP measurements and retrograde labeling experiments show that the number of RGCs is reduced whereas the remaining RGCs and axons function normally. Taken together, these findings support an ascending progress of degeneration from the soma toward the axon.
authors.affiliation: Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tübingen, Tübingen, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Heiduschka
authors.forename: Sven
authors.initials: S
authors.lastname: Schnichels
authors.forename: Nico
authors.initials: N
authors.lastname: Fuhrmann
authors.forename: Sabine
authors.initials: S
authors.lastname: Hofmeister
authors.forename: Ulrich
authors.initials: U
authors.lastname: Schraermeyer
authors.forename: Bernd
authors.initials: B
authors.lastname: Wissinger
authors.forename: Marcel V
authors.initials: MV
authors.lastname: Alavi
mesh_terms: D000818:Animals; D001370:Axonal Transport / Q000502:physiology; D002452:Cell Count; D002470:Cell Survival; D004195:Disease Models, Animal; D004596:Electroretinography; D005074:Evoked Potentials, Visual / Q000502:physiology*; D005456:Fluorescent Dyes / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000235:genetics*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D029241:Optic Atrophy, Autosomal Dominant / Q000235:genetics / Q000503:physiopathology*; D009900:Optic Nerve / Q000503:physiopathology*; D012160:Retina / Q000503:physiopathology*; D012165:Retinal Ganglion Cells / Q000473:pathology*; D013266:Stilbamidines / Q000378:metabolism; D014792:Visual Acuity / Q000502:physiology
chemical_list: C049774:2-hydroxy-4,4'-diamidinostilbene, methanesulfonate salt; D005456:Fluorescent Dyes; D013266:Stilbamidines; D020558:GTP Phosphohydrolases; C498809:Opa1 protein, mouse