title: CNGA3 deficiency affects cone synaptic terminal structure and function and leads to secondary rod dysfunction and degeneration.
abstract: OBJECTIVE
  To investigate rod function and survival after cone dysfunction and degeneration in a mouse model of cone cyclic nucleotide-gated (CNG) channel deficiency.
  
  
  METHODS
  Rod function and survival in mice with cone CNG channel subunit CNGA3 deficiency (CNGA3-/- mice) were evaluated by electroretinographic (ERG), morphometric, and Western blot analyses. The arrangement, integrity, and ultrastructure of photoreceptor terminals were investigated by immunohistochemistry and electron microscopy.
  
  
  RESULTS
  The authors found loss of cone function and cone death accompanied by impairment of rods and rod-driven signaling in CNGA3-/- mice. Scotopic ERG b-wave amplitudes were reduced by 15% at 1 month, 30% at 6 months, and 40% at 9 months and older, while scotopic a-wave amplitudes were decreased by 20% at 9 months, compared with ERGs of age-matched wild-type mice. Outer nuclear layer thickness in CNGA3-/- retina was reduced by 15% at 12 months compared with age-matched wild-type controls. This was accompanied by a 30%-40% reduction in expression of rod-specific proteins, including rhodopsin, rod transducin α-subunit, and glutamic acid-rich protein (GARP). Cone terminals in the CNGA3-/- retina showed a progressive loss of neurochemical and ultrastructural integrity. Abnormalities were observed as early as 1 month. Disorganized rod terminal ultrastructure was noted by 12 months.
  
  
  CONCLUSIONS
  These findings demonstrate secondary rod impairment and degeneration after cone degeneration in mice with cone CNG channel deficiency. Loss of cone phototransduction accompanies the compromised integrity of cone terminals. With time, rod synaptic structure, function, and viability also become compromised.
authors.affiliation: Department of Cell Biology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Xu
authors.forename: Lynsie M
authors.initials: LM
authors.lastname: Morris
authors.forename: Stylianos
authors.initials: S
authors.lastname: Michalakis
authors.forename: Martin
authors.initials: M
authors.lastname: Biel
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Fliesler
authors.forename: David M
authors.initials: DM
authors.lastname: Sherry
authors.forename: Xi-Qin
authors.initials: XQ
authors.lastname: Ding
mesh_terms: D000818:Animals; D019393:Arrestin / Q000378:metabolism; D015153:Blotting, Western; D002470:Cell Survival; D054815:Cyclic Nucleotide-Gated Cation Channels / Q000172:deficiency*; D004596:Electroretinography; D020962:Heterotrimeric GTP-Binding Proteins / Q000378:metabolism; D007150:Immunohistochemistry; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008854:Microscopy, Electron; D017729:Presynaptic Terminals / Q000648:ultrastructure*; D017949:Retinal Cone Photoreceptor Cells / Q000378:metabolism / Q000473:pathology*; D012162:Retinal Degeneration / Q000503:physiopathology*; D017948:Retinal Rod Photoreceptor Cells / Q000378:metabolism / Q000473:pathology*; D012243:Rhodopsin / Q000378:metabolism; D017299:Rod Opsins / Q000378:metabolism; D015293:Transducin / Q000378:metabolism; D014785:Vision, Ocular
chemical_list: D019393:Arrestin; C518237:Cnga3 protein, mouse; D054815:Cyclic Nucleotide-Gated Cation Channels; C515337:Gnat2 protein, mouse; C484196:Lrrc32 protein, mouse; D008565:Membrane Proteins; D017299:Rod Opsins; C095854:middle-wavelength opsin; D012243:Rhodopsin; D020962:Heterotrimeric GTP-Binding Proteins; D015293:Transducin